Detailed studies of gene transcription regulation in a wide variety of eukaryotic systems has revealed the general principles and mechanisms by which cell- or tissue-specific regulation of differential gene transcription is mediated (reviewed in Naar, 2001. Kadonaga, 2004, Maston, 2006, Barolo, 2002; Roeder, 2005, Rosenfeld, 2006). Of the three major classes of DNA polymerase involved in eukaryotic gene transcription, Polymerase II generally regulates protein-encoding genes. Figure 1 shows a diagram of the various components involved in cell-specific regulation of Pol-II gene transcription.
Core Promoter: Pol II-regulated genes typically have a Core Promoter where Pol II and a variety of general factors bind to specific DNA motifs: i: the TATA box (TATA DNA sequence), which is bound by the "TATA-binding protein" (TBP). ii: the Initiator motif (INR), where Pol II and certain other core factors bind, is present in many Pol II-regulated genes. iii: the Downstream Promoter Element (DPE), which is present in a subset of Pol II genes, and where additional core factors bind. The core promoter binding factors are generally ubiquitously expressed, although there are exceptions to this.
Proximal Promoter: immediately upstream (5') of the core promoter, Pol II target genes often have a Proximal Promoter region that spans up to 500 base pairs (b.p.), or even to 1000 b.p.. This region contains a number of functional DNA binding sites for a specific set of transcription activator (TA) and transcription repressor (TR) proteins. These TA and TR factors are generally cell- or tissue-specific in expression, rather than ubiquitous, so that the presence of their cognate binding sites in the proximal promoter region programs cell- or tissue-specific expression of the target gene, perhaps in conjunction with TA and TR complexes bound in distal enhancer regions.
Distal Enhancer(s): many or most Pol II regulated genes in higher eukaryotes have one or more distal Enhancer regions which are essential for proper regulation of the gene, often in a cell or tissue-specific pattern. Like the proximal promoter region, each of the distal enhancer regions typically contain a cluster of binding sites for specific TA and/or TR DNA-binding factors, rather than just a single site.
Enhancers generally have three defining characteristics: i: They can be located very long distances from the promoter of the target gene they regulate, sometimes as far as 100 Kb, or more. ii: They can be either upstream (5') or downstream (3') of the target gene, including within introns of that gene. iii: They can function in either orientation in the DNA.
Combinatorial mechanisms of transcription regulation: The specific combination of TA and TR binding sites within the proximal promoter and/or distal enhancer(s) provides a "combinatorial transcription code" that mediates cell- or tissue-specific expression of the associated target gene. Each promoter or enhancer region mediates expression in a specific subset of the overall expression pattern. In at least some cases, each enhancer region functions completely independently of the others, so that the overall expression pattern is a linear combination of the expression patterns of each of the enhancer modules.
Co-Activator and Co-Repressor Complexes: DNA-bound TA and TR proteins typically recruit the assembly of specific Co-Activator (Co-A) and Co-Repressor (Co-R) Complexes, respectively, which are essential for regulating target gene transcription. Both Co-A's and Co-R's are multi-protein complexes that contain several specific protein components.
Co-Activator complexes generally contain at lease one component protein that has Histone Acetyl Transferase (HAT) enzymatic activity. This functions to acetylate Histones and/or other chromatin-associated factors, which typically increases that transcription activation of the target gene. By contrast, Co-Repressor complexes generally contain at lease one component protein that has Histone De-Acetylase (HDAC) enzymatic activity. This functions to de-acetylate Histones and/or other chromatin-associated factors. This typically increases the transcription repression of the target gene.
Adaptor (Mediator) complexes: In addition to the co-activator complexes that assemble on particular cell-specific TA factors, - there are at least two additional transcriptional co-activator complexes common to most cells. One of these is the Mediator complex, which functions as an "adaptor" complex that bridges between the tissue-specific co-activator complexes assembled in the proximal promoter (or distal enhancers). The human Mediator complex has been shown to contain at least 19 protein distinct components. Different combinations of these co-activator proteins are also found to be components of specific transcription Co-Activator complexes, such as the DRIP, TRAP and ARC complexes described below.
TBP/TAF complex: Another large Co-A complex is the "TBP-associated factors" (TAFs) that assemble on TBP (TATA-Binding Protein), which is bound to the TATA box present in many promoters. There are at least 23 human TAF proteins that have been identified. Many of these are ubiquitously expressed, but TAFs can also be expressed in a cell or tissue-specific pattern.
Specific Coactivator Complexes for DNA-binding Transcription Factors.
A number of specific co-activator complexes for DNA-binding transcription factors have been identified, including DRIP, TRAP, and ARC (reviewed in Bourbon, 2004, Blazek, 2005, Conaway, 2005, and Malik, 2005). The DRIP co-activator complex was originally identified and named as a specific complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). Similarly, the TRAP co-activator complex was originally identified as a complex that associates with the thyroid receptor (Yuan, 1998). It was later determined that all of the components of the DRIP complex are also present in the TRAP complex, and the ARC complex (discussed further below). For example, the DRIP205 and TRAP220 proteins were show to be identical, as were specific pairs of the other components of these complexes (Rachez, 1999).
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator ("adaptor") complex proteins (reviewed in Bourbon, 2004). The Mediator proteins were originally identified in yeast by Kornberg and colleagues, as complexes associated with DNA polymerase (Kelleher, 1990). In higher organisms, Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (Figure 1). However, many of the Mediator homologues can also be found in complexes associated with specific transcription factors in higher organisms. A unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004). For example, the DRIP205 / TRAP220 proteins are now identified as Mediator 1 (Rachez, 1999), based on homology with yeast Mediator 1.
Example Pathway: Specific Regulation of Target Genes During Notch Signaling:
One well-studied example of cell-specific regulation of gene transcription is selective regulation of target genes during Notch signaling. Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL.
In Drosophila, Su(H) is known to be bifunctional, in that it represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.
Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).
In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila.
During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus (Figure 2). Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-R complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002).
Thus, CSL is a good example of a bifunctional DNA-binding transcription factor that mediates repression of specific targets genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=212436
Franklin TB, Russig H, Weiss IC, Gräff J, Linder N, Michalon A, Vizi S, Mansuy IM.; ''Epigenetic transmission of the impact of early stress across generations.''; PubMedEurope PMCScholia
KhorshidAhmad T, Acosta C, Cortes C, Lakowski TM, Gangadaran S, Namaka M.; ''Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS).''; PubMedEurope PMCScholia
Williamson SL, Ellaway CJ, Peters GB, Pelka GJ, Tam PP, Christodoulou J.; ''Deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype.''; PubMedEurope PMCScholia
Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Näär AM, Erdjument-Bromage H, Tempst P, Freedman LP.; ''Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex.''; PubMedEurope PMCScholia
Ito Y, Bae SC, Chuang LS.; ''The RUNX family: developmental regulators in cancer.''; PubMedEurope PMCScholia
Impens F, Radoshevich L, Cossart P, Ribet D.; ''Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuli.''; PubMedEurope PMCScholia
Underwood KF, D'Souza DR, Mochin-Peters M, Pierce AD, Kommineni S, Choe M, Bennett J, Gnatt A, Habtemariam B, MacKerell AD, Passaniti A.; ''Regulation of RUNX2 transcription factor-DNA interactions and cell proliferation by vitamin D3 (cholecalciferol) prohormone activity.''; PubMedEurope PMCScholia
Chimge NO, Frenkel B.; ''The RUNX family in breast cancer: relationships with estrogen signaling.''; PubMedEurope PMCScholia
McGill BE, Bundle SF, Yaylaoglu MB, Carson JP, Thaller C, Zoghbi HY.; ''Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome.''; PubMedEurope PMCScholia
Gao H, Le Y, Wu X, Silberstein LE, Giese RW, Zhu Z.; ''VentX, a novel lymphoid-enhancing factor/T-cell factor-associated transcription repressor, is a putative tumor suppressor.''; PubMedEurope PMCScholia
Otto F, Kanegane H, Mundlos S.; ''Mutations in the RUNX2 gene in patients with cleidocranial dysplasia.''; PubMedEurope PMCScholia
Roeder RG.; ''Transcriptional regulation and the role of diverse coactivators in animal cells.''; PubMedEurope PMCScholia
Samaco RC, Mandel-Brehm C, McGraw CM, Shaw CA, McGill BE, Zoghbi HY.; ''Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome.''; PubMedEurope PMCScholia
Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K, Klose RJ, Schanen C, Jaenisch R, Wang W, Sun YE.; ''Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function.''; PubMedEurope PMCScholia
Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G.; ''Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.''; PubMedEurope PMCScholia
Bourbon HM, Aguilera A, Ansari AZ, Asturias FJ, Berk AJ, Bjorklund S, Blackwell TK, Borggrefe T, Carey M, Carlson M, Conaway JW, Conaway RC, Emmons SW, Fondell JD, Freedman LP, Fukasawa T, Gustafsson CM, Han M, He X, Herman PK, Hinnebusch AG, Holmberg S, Holstege FC, Jaehning JA, Kim YJ, Kuras L, Leutz A, Lis JT, Meisterernest M, Naar AM, Nasmyth K, Parvin JD, Ptashne M, Reinberg D, Ronne H, Sadowski I, Sakurai H, Sipiczki M, Sternberg PW, Stillman DJ, Strich R, Struhl K, Svejstrup JQ, Tuck S, Winston F, Roeder RG, Kornberg RD.; ''A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II.''; PubMedEurope PMCScholia
Onichtchouk D, Gawantka V, Dosch R, Delius H, Hirschfeld K, Blumenstock C, Niehrs C.; ''The Xvent-2 homeobox gene is part of the BMP-4 signalling pathway controlling [correction of controling] dorsoventral patterning of Xenopus mesoderm.''; PubMedEurope PMCScholia
Kammerer M, Gutzwiller S, Stauffer D, Delhon I, Seltenmeyer Y, Fournier B.; ''Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα) are both transcriptional regulators of the Runx2-I isoform.''; PubMedEurope PMCScholia
Ding X, Luo C, Zhou J, Zhong Y, Hu X, Zhou F, Ren K, Gan L, He A, Zhu J, Gao X, Zhang J.; ''The interaction of KCTD1 with transcription factor AP-2alpha inhibits its transactivation.''; PubMedEurope PMCScholia
Hwang CK, Kim CS, Kim DK, Law PY, Wei LN, Loh HH.; ''Up-regulation of the mu-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells.''; PubMedEurope PMCScholia
Trimarchi JM, Fairchild B, Verona R, Moberg K, Andon N, Lees JA.; ''E2F-6, a member of the E2F family that can behave as a transcriptional repressor.''; PubMedEurope PMCScholia
Hu K, Nan X, Bird A, Wang W.; ''Testing for association between MeCP2 and the brahma-associated SWI/SNF chromatin-remodeling complex.''; PubMedEurope PMCScholia
Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y.; ''A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells.''; PubMedEurope PMCScholia
Nishina S, Shiraha H, Nakanishi Y, Tanaka S, Matsubara M, Takaoka N, Uemura M, Horiguchi S, Kataoka J, Iwamuro M, Yagi T, Yamamoto K.; ''Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling.''; PubMedEurope PMCScholia
Lam K, Zhang DE.; ''RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis.''; PubMedEurope PMCScholia
Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M, Putti TC, Loh M, Ko TK, Huang C, Bhalla KN, Zhu T, Ito Y, Sukumar S.; ''RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer.''; PubMedEurope PMCScholia
Bogachek MV, Chen Y, Kulak MV, Woodfield GW, Cyr AR, Park JM, Spanheimer PM, Li Y, Li T, Weigel RJ.; ''Sumoylation pathway is required to maintain the basal breast cancer subtype.''; PubMedEurope PMCScholia
Ogihara Y, Masuda T, Ozaki S, Yoshikawa M, Shiga T.; ''Runx3-regulated expression of two Ntrk3 transcript variants in dorsal root ganglion neurons.''; PubMedEurope PMCScholia
Zhao X, Chen A, Yan X, Zhang Y, He F, Hayashi Y, Dong Y, Rao Y, Li B, Conway RM, Maiques-Diaz A, Elf SE, Huang N, Zuber J, Xiao Z, Tse W, Tenen DG, Wang Q, Chen W, Mulloy JC, Nimer SD, Huang G.; ''Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal.''; PubMedEurope PMCScholia
Robledo RF, Rajan L, Li X, Lufkin T.; ''The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development.''; PubMedEurope PMCScholia
Zhong YF, Holland PW.; ''The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages.''; PubMedEurope PMCScholia
Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW.; ''CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.''; PubMedEurope PMCScholia
Oberley MJ, Inman DR, Farnham PJ.; ''E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9.''; PubMedEurope PMCScholia
Fryer CJ, White JB, Jones KA.; ''Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.''; PubMedEurope PMCScholia
Rachez C, Suldan Z, Ward J, Chang CP, Burakov D, Erdjument-Bromage H, Tempst P, Freedman LP.; ''A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system.''; PubMedEurope PMCScholia
Maston GA, Evans SK, Green MR.; ''Transcriptional regulatory elements in the human genome.''; PubMedEurope PMCScholia
Chi XZ, Yang JO, Lee KY, Ito K, Sakakura C, Li QL, Kim HR, Cha EJ, Lee YH, Kaneda A, Ushijima T, Kim WJ, Ito Y, Bae SC.; ''RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD.''; PubMedEurope PMCScholia
Livide G, Patriarchi T, Amenduni M, Amabile S, Yasui D, Calcagno E, Lo Rizzo C, De Falco G, Ulivieri C, Ariani F, Mari F, Mencarelli MA, Hell JW, Renieri A, Meloni I.; ''GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.''; PubMedEurope PMCScholia
Accili D, Arden KC.; ''FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.''; PubMedEurope PMCScholia
Durand S, Patrizi A, Quast KB, Hachigian L, Pavlyuk R, Saxena A, Carninci P, Hensch TK, Fagiolini M.; ''NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2.''; PubMedEurope PMCScholia
Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J.; ''N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso.''; PubMedEurope PMCScholia
Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH.; ''Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice.''; PubMedEurope PMCScholia
Wang X, Blagden C, Fan J, Nowak SJ, Taniuchi I, Littman DR, Burden SJ.; ''Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle.''; PubMedEurope PMCScholia
Yasui DH, Gonzales ML, Aflatooni JO, Crary FK, Hu DJ, Gavino BJ, Golub MS, Vincent JB, Carolyn Schanen N, Olson CO, Rastegar M, Lasalle JM.; ''Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.''; PubMedEurope PMCScholia
Pierce AD, Anglin IE, Vitolo MI, Mochin MT, Underwood KF, Goldblum SE, Kommineni S, Passaniti A.; ''Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype.''; PubMedEurope PMCScholia
Tsujimura K, Irie K, Nakashima H, Egashira Y, Fukao Y, Fujiwara M, Itoh M, Uesaka M, Imamura T, Nakahata Y, Yamashita Y, Abe T, Takamori S, Nakashima K.; ''miR-199a Links MeCP2 with mTOR Signaling and Its Dysregulation Leads to Rett Syndrome Phenotypes.''; PubMedEurope PMCScholia
Shigesada K, van de Sluis B, Liu PP.; ''Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11.''; PubMedEurope PMCScholia
Imai Y, Gates MA, Melby AE, Kimelman D, Schier AF, Talbot WS.; ''The homeobox genes vox and vent are redundant repressors of dorsal fates in zebrafish.''; PubMedEurope PMCScholia
Berlato C, Chan KV, Price AM, Canosa M, Scibetta AG, Hurst HC.; ''Alternative TFAP2A isoforms have distinct activities in breast cancer.''; PubMedEurope PMCScholia
Kovall RA.; ''Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex.''; PubMedEurope PMCScholia
Kimura H, Shiota K.; ''Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1.''; PubMedEurope PMCScholia
Kanno T, Kanno Y, Chen LF, Ogawa E, Kim WY, Ito Y.; ''Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit.''; PubMedEurope PMCScholia
Scerbo P, Marchal L, Kodjabachian L.; ''Lineage commitment of embryonic cells involves MEK1-dependent clearance of pluripotency regulator Ventx2.''; PubMedEurope PMCScholia
Gao J, Chen Y, Wu KC, Liu J, Zhao YQ, Pan YL, Du R, Zheng GR, Xiong YM, Xu HL, Fan DM.; ''RUNX3 directly interacts with intracellular domain of Notch1 and suppresses Notch signaling in hepatocellular carcinoma cells.''; PubMedEurope PMCScholia
Eijkelenboom A, Burgering BM.; ''FOXOs: signalling integrators for homeostasis maintenance.''; PubMedEurope PMCScholia
Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH, Stein GS, Liu PP.; ''Cbfbeta interacts with Runx2 and has a critical role in bone development.''; PubMedEurope PMCScholia
Wang D, Shin TH, Kudlow JE.; ''Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene.''; PubMedEurope PMCScholia
Plummer JT, Evgrafov OV, Bergman MY, Friez M, Haiman CA, Levitt P, Aldinger KA.; ''Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.''; PubMedEurope PMCScholia
Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P, Fryns JP, Froyen G.; ''Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males.''; PubMedEurope PMCScholia
Bertoli C, Klier S, McGowan C, Wittenberg C, de Bruin RA.; ''Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription.''; PubMedEurope PMCScholia
Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B.; ''Dominance of SOX9 function over RUNX2 during skeletogenesis.''; PubMedEurope PMCScholia
Harikrishnan KN, Chow MZ, Baker EK, Pal S, Bassal S, Brasacchio D, Wang L, Craig JM, Jones PL, Sif S, El-Osta A.; ''Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing.''; PubMedEurope PMCScholia
Blazek E, Mittler G, Meisterernst M.; ''The mediator of RNA polymerase II.''; PubMedEurope PMCScholia
Melnikova VO, Dobroff AS, Zigler M, Villares GJ, Braeuer RR, Wang H, Huang L, Bar-Eli M.; ''CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma.''; PubMedEurope PMCScholia
Zhang YY, Li X, Qian SW, Guo L, Huang HY, He Q, Liu Y, Ma CG, Tang QQ.; ''Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis.''; PubMedEurope PMCScholia
McPherson LA, Weigel RJ.; ''AP2alpha and AP2gamma: a comparison of binding site specificity and trans-activation of the estrogen receptor promoter and single site promoter constructs.''; PubMedEurope PMCScholia
Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, Goldenberg D, Negreanu V, Bernstein Y, Levanon D, Jung S, Groner Y.; ''Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation.''; PubMedEurope PMCScholia
Huang B, Qu Z, Ong CW, Tsang YH, Xiao G, Shapiro D, Salto-Tellez M, Ito K, Ito Y, Chen LF.; ''RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α.''; PubMedEurope PMCScholia
Jepsen K, Rosenfeld MG.; ''Biological roles and mechanistic actions of co-repressor complexes.''; PubMedEurope PMCScholia
Zarelli VE, Dawid IB.; ''Inhibition of neural crest formation by Kctd15 involves regulation of transcription factor AP-2.''; PubMedEurope PMCScholia
Wu X, Gao H, Bleday R, Zhu Z.; ''Homeobox transcription factor VentX regulates differentiation and maturation of human dendritic cells.''; PubMedEurope PMCScholia
Vousden KH, Prives C.; ''Blinded by the Light: The Growing Complexity of p53.''; PubMedEurope PMCScholia
Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG.; ''The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion.''; PubMedEurope PMCScholia
Storre J, Elsässer HP, Fuchs M, Ullmann D, Livingston DM, Gaubatz S.; ''Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6.''; PubMedEurope PMCScholia
LiCalsi C, Christophe S, Steger DJ, Buescher M, Fischer W, Mellon PL.; ''AP-2 family members regulate basal and cAMP-induced expression of human chorionic gonadotropin.''; PubMedEurope PMCScholia
Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, Hu M, Davis CM, Wang J, Brunicardi FC, Shi Y, Chen YG, Meng A, Feng XH.; ''PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.''; PubMedEurope PMCScholia
Joss-Moore LA, Wang Y, Ogata EM, Sainz AJ, Yu X, Callaway CW, McKnight RA, Albertine KH, Lane RH.; ''IUGR differentially alters MeCP2 expression and H3K9Me3 of the PPARγ gene in male and female rat lungs during alveolarization.''; PubMedEurope PMCScholia
Dragich JM, Kim YH, Arnold AP, Schanen NC.; ''Differential distribution of the MeCP2 splice variants in the postnatal mouse brain.''; PubMedEurope PMCScholia
Maezawa I, Jin LW.; ''Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate.''; PubMedEurope PMCScholia
Puig-Kröger A, Aguilera-Montilla N, Martínez-Nuñez R, Domínguez-Soto A, Sánchez-Cabo F, Martín-Gayo E, Zaballos A, Toribio ML, Groner Y, Ito Y, Dopazo A, Corcuera MT, Alonso Martín MJ, Vega MA, Corbí AL.; ''The novel RUNX3/p33 isoform is induced upon monocyte-derived dendritic cell maturation and downregulates IL-8 expression.''; PubMedEurope PMCScholia
Cheng TL, Wang Z, Liao Q, Zhu Y, Zhou WH, Xu W, Qiu Z.; ''MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.''; PubMedEurope PMCScholia
Umair Z, Kumar S, Kim DH, Rafiq K, Kumar V, Kim S, Park JB, Lee JY, Lee U, Kim J.; ''Ventx1.1 as a Direct Repressor of Early Neural Gene zic3 in Xenopus laevis.''; PubMedEurope PMCScholia
Long F.; ''Building strong bones: molecular regulation of the osteoblast lineage.''; PubMedEurope PMCScholia
Le Marer N.; ''GALECTIN-3 expression in differentiating human myeloid cells.''; PubMedEurope PMCScholia
Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Flannery R, Jaenisch R, Sur M.; ''Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice.''; PubMedEurope PMCScholia
Sztainberg Y, Chen HM, Swann JW, Hao S, Tang B, Wu Z, Tang J, Wan YW, Liu Z, Rigo F, Zoghbi HY.; ''Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.''; PubMedEurope PMCScholia
Scibetta AG, Wong PP, Chan KV, Canosa M, Hurst HC.; ''Dual association by TFAP2A during activation of the p21cip/CDKN1A promoter.''; PubMedEurope PMCScholia
Davidson AJ, Zon LI.; ''Turning mesoderm into blood: the formation of hematopoietic stem cells during embryogenesis.''; PubMedEurope PMCScholia
Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, Mann DA.; ''MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis.''; PubMedEurope PMCScholia
Wu X, Gao H, Ke W, Hager M, Xiao S, Freeman MR, Zhu Z.; ''VentX trans-activates p53 and p16ink4a to regulate cellular senescence.''; PubMedEurope PMCScholia
He LJ, Liu N, Cheng TL, Chen XJ, Li YD, Shu YS, Qiu ZL, Zhang XH.; ''Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity.''; PubMedEurope PMCScholia
Ebihara T, Ebihara T, Song C, Ryu SH, Plougastel-Douglas B, Yang L, Levanon D, Groner Y, Bern MD, Stappenbeck TS, Colonna M, Egawa T, Yokoyama WM.; ''Runx3 specifies lineage commitment of innate lymphoid cells.''; PubMedEurope PMCScholia
Orlic-Milacic M, Kaufman L, Mikhailov A, Cheung AY, Mahmood H, Ellis J, Gianakopoulos PJ, Minassian BA, Vincent JB.; ''Over-expression of either MECP2_e1 or MECP2_e2 in neuronally differentiated cells results in different patterns of gene expression.''; PubMedEurope PMCScholia
Li Y, Wang H, Muffat J, Cheng AW, Orlando DA, Lovén J, Kwok SM, Feldman DA, Bateup HS, Gao Q, Hockemeyer D, Mitalipova M, Lewis CA, Vander Heiden MG, Sur M, Young RA, Jaenisch R.; ''Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons.''; PubMedEurope PMCScholia
Qiao Y, Lin SJ, Chen Y, Voon DC, Zhu F, Chuang LS, Wang T, Tan P, Lee SC, Yeoh KG, Sudol M, Ito Y.; ''RUNX3 is a novel negative regulator of oncogenic TEAD-YAP complex in gastric cancer.''; PubMedEurope PMCScholia
Li QL, Ito K, Sakakura C, Fukamachi H, Inoue Ki, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y.; ''Causal relationship between the loss of RUNX3 expression and gastric cancer.''; PubMedEurope PMCScholia
Jaruga A, Hordyjewska E, Kandzierski G, Tylzanowski P.; ''Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation.''; PubMedEurope PMCScholia
Cyr AR, Kulak MV, Park JM, Bogachek MV, Spanheimer PM, Woodfield GW, White-Baer LS, O'Malley YQ, Sugg SL, Olivier AK, Zhang W, Domann FE, Weigel RJ.; ''TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis.''; PubMedEurope PMCScholia
Domínguez-Soto A, Relloso M, Vega MA, Corbí AL, Puig-Kröger A.; ''RUNX3 regulates the activity of the CD11a and CD49d integrin gene promoters.''; PubMedEurope PMCScholia
Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD.; ''SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.''; PubMedEurope PMCScholia
Reis BS, Rogoz A, Costa-Pinto FA, Taniuchi I, Mucida D.; ''Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4⁺ T cell immunity.''; PubMedEurope PMCScholia
Wilson JJ, Kovall RA.; ''Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA.''; PubMedEurope PMCScholia
Inoue K, Ozaki S, Shiga T, Ito K, Masuda T, Okado N, Iseda T, Kawaguchi S, Ogawa M, Bae SC, Yamashita N, Itohara S, Kudo N, Ito Y.; ''Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons.''; PubMedEurope PMCScholia
Wotton D, Lo RS, Lee S, Massagué J.; ''A Smad transcriptional corepressor.''; PubMedEurope PMCScholia
Li W, Calfa G, Larimore J, Pozzo-Miller L.; ''Activity-dependent BDNF release and TRPC signaling is impaired in hippocampal neurons of Mecp2 mutant mice.''; PubMedEurope PMCScholia
Friedman JR, Fredericks WJ, Jensen DE, Speicher DW, Huang XP, Neilson EG, Rauscher FJ.; ''KAP-1, a novel corepressor for the highly conserved KRAB repression domain.''; PubMedEurope PMCScholia
Yoshida CA, Furuichi T, Fujita T, Fukuyama R, Kanatani N, Kobayashi S, Satake M, Takada K, Komori T.; ''Core-binding factor beta interacts with Runx2 and is required for skeletal development.''; PubMedEurope PMCScholia
Feldman D, Banerjee A, Sur M.; ''Developmental Dynamics of Rett Syndrome.''; PubMedEurope PMCScholia
Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y, Olaru A, Wang S, Mori Y, Deacu E, Hamilton J, Kan T, Krasna MJ, Beer DG, Pepe MS, Abraham JM, Feng Z, Schmiegel W, Greenwald BD, Meltzer SJ.; ''Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk.''; PubMedEurope PMCScholia
Lengner CJ, Hassan MQ, Serra RW, Lepper C, van Wijnen AJ, Stein JL, Lian JB, Stein GS.; ''Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation.''; PubMedEurope PMCScholia
Williams T, Tjian R.; ''Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins.''; PubMedEurope PMCScholia
Urdinguio RG, Lopez-Serra L, Lopez-Nieva P, Alaminos M, Diaz-Uriarte R, Fernandez AF, Esteller M.; ''Mecp2-null mice provide new neuronal targets for Rett syndrome.''; PubMedEurope PMCScholia
Eckert D, Buhl S, Weber S, Jäger R, Schorle H.; ''The AP-2 family of transcription factors.''; PubMedEurope PMCScholia
Bertoli C, Herlihy AE, Pennycook BR, Kriston-Vizi J, de Bruin RAM.; ''Sustained E2F-Dependent Transcription Is a Key Mechanism to Prevent Replication-Stress-Induced DNA Damage.''; PubMedEurope PMCScholia
Olson CO, Zachariah RM, Ezeonwuka CD, Liyanage VR, Rastegar M.; ''Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements.''; PubMedEurope PMCScholia
Cai X, Gao L, Teng L, Ge J, Oo ZM, Kumar AR, Gilliland DG, Mason PJ, Tan K, Speck NA.; ''Runx1 Deficiency Decreases Ribosome Biogenesis and Confers Stress Resistance to Hematopoietic Stem and Progenitor Cells.''; PubMedEurope PMCScholia
Williams T, Tjian R.; ''Analysis of the DNA-binding and activation properties of the human transcription factor AP-2.''; PubMedEurope PMCScholia
Oh H, Irvine KD.; ''Yorkie: the final destination of Hippo signaling.''; PubMedEurope PMCScholia
Krishnan N, Krishnan K, Connors CR, Choy MS, Page R, Peti W, Van Aelst L, Shea SD, Tonks NK.; ''PTP1B inhibition suggests a therapeutic strategy for Rett syndrome.''; PubMedEurope PMCScholia
Yang DC, Yang MH, Tsai CC, Huang TF, Chen YH, Hung SC.; ''Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST.''; PubMedEurope PMCScholia
Mortus JR, Zhang Y, Hughes DP.; ''Developmental pathways hijacked by osteosarcoma.''; PubMedEurope PMCScholia
Rosenfeld MG, Lunyak VV, Glass CK.; ''Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response.''; PubMedEurope PMCScholia
Lee MH, Kim YJ, Yoon WJ, Kim JI, Kim BG, Hwang YS, Wozney JM, Chi XZ, Bae SC, Choi KY, Cho JY, Choi JY, Ryoo HM.; ''Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter.''; PubMedEurope PMCScholia
Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G.; ''A twist code determines the onset of osteoblast differentiation.''; PubMedEurope PMCScholia
Bamforth SD, Bragança J, Eloranta JJ, Murdoch JN, Marques FI, Kranc KR, Farza H, Henderson DJ, Hurst HC, Bhattacharya S.; ''Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator.''; PubMedEurope PMCScholia
Barolo S, Posakony JW.; ''Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling.''; PubMedEurope PMCScholia
Li XQ, Du X, Li DM, Kong PZ, Sun Y, Liu PF, Wang QS, Feng YM.; ''ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway.''; PubMedEurope PMCScholia
Turner BC, Zhang J, Gumbs AA, Maher MG, Kaplan L, Carter D, Glazer PM, Hurst HC, Haffty BG, Williams T.; ''Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways.''; PubMedEurope PMCScholia
Ducy P, Karsenty G.; ''Two distinct osteoblast-specific cis-acting elements control expression of a mouse osteocalcin gene.''; PubMedEurope PMCScholia
Gaubatz S, Wood JG, Livingston DM.; ''Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6.''; PubMedEurope PMCScholia
Kaddoum L, Panayotis N, Mazarguil H, Giglia-Mari G, Roux JC, Joly E.; ''Isoform-specific anti-MeCP2 antibodies confirm that expression of the e1 isoform strongly predominates in the brain.''; PubMedEurope PMCScholia
deConinck EC, McPherson LA, Weigel RJ.; ''Transcriptional regulation of estrogen receptor in breast carcinomas.''; PubMedEurope PMCScholia
Roca H, Phimphilai M, Gopalakrishnan R, Xiao G, Franceschi RT.; ''Cooperative interactions between RUNX2 and homeodomain protein-binding sites are critical for the osteoblast-specific expression of the bone sialoprotein gene.''; PubMedEurope PMCScholia
Leong WY, Lim ZH, Korzh V, Pietri T, Goh EL.; ''Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2.''; PubMedEurope PMCScholia
Louvi A, Artavanis-Tsakonas S.; ''Notch signalling in vertebrate neural development.''; PubMedEurope PMCScholia
Dhillon VS, Shahid M, Husain SA.; ''CpG methylation of the FHIT, FANCF, cyclin-D2, BRCA2 and RUNX3 genes in Granulosa cell tumors (GCTs) of ovarian origin.''; PubMedEurope PMCScholia
Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L, Inui M, Moro S, Modena N, Argenton F, Newfeld SJ, Piccolo S.; ''FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.''; PubMedEurope PMCScholia
Ryan RF, Schultz DC, Ayyanathan K, Singh PB, Friedman JR, Fredericks WJ, Rauscher FJ.; ''KAP-1 corepressor protein interacts and colocalizes with heterochromatic and euchromatic HP1 proteins: a potential role for Krüppel-associated box-zinc finger proteins in heterochromatin-mediated gene silencing.''; PubMedEurope PMCScholia
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A.; ''Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.''; PubMedEurope PMCScholia
Wong PP, Miranda F, Chan KV, Berlato C, Hurst HC, Scibetta AG.; ''Histone demethylase KDM5B collaborates with TFAP2C and Myc to repress the cell cycle inhibitor p21(cip) (CDKN1A).''; PubMedEurope PMCScholia
De Andrade JP, Park JM, Gu VW, Woodfield GW, Kulak MV, Lorenzen AW, Wu VT, Van Dorin SE, Spanheimer PM, Weigel RJ.; ''EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib.''; PubMedEurope PMCScholia
Mangan JK, Speck NA.; ''RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making.''; PubMedEurope PMCScholia
Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY.; ''Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.''; PubMedEurope PMCScholia
Scerbo P, Girardot F, Vivien C, Markov GV, Luxardi G, Demeneix B, Kodjabachian L, Coen L.; ''Ventx factors function as Nanog-like guardians of developmental potential in Xenopus.''; PubMedEurope PMCScholia
Kramer I, Sigrist M, de Nooij JC, Taniuchi I, Jessell TM, Arber S.; ''A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.''; PubMedEurope PMCScholia
Tribioli C, Lufkin T.; ''The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen.''; PubMedEurope PMCScholia
Kruiswijk F, Labuschagne CF, Vousden KH.; ''p53 in survival, death and metabolic health: a lifeguard with a licence to kill.''; PubMedEurope PMCScholia
Li Q, Pan H, Guan L, Su D, Ma X.; ''CITED2 mutation links congenital heart defects to dysregulation of the cardiac gene VEGF and PITX2C expression.''; PubMedEurope PMCScholia
Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G.; ''A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development.''; PubMedEurope PMCScholia
Chen CR, Kang Y, Siegel PM, Massagué J.; ''E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression.''; PubMedEurope PMCScholia
Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q.; ''Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain.''; PubMedEurope PMCScholia
Levkovitz L, Yosef N, Gershengorn MC, Ruppin E, Sharan R, Oron Y.; ''A novel HMM-based method for detecting enriched transcription factor binding sites reveals RUNX3 as a potential target in pancreatic cancer biology.''; PubMedEurope PMCScholia
Arman M, Aguilera-Montilla N, Mas V, Puig-Kröger A, Pignatelli M, Guigó R, Corbí AL, Lozano F.; ''The human CD6 gene is transcriptionally regulated by RUNX and Ets transcription factors in T cells.''; PubMedEurope PMCScholia
Hwang CK, Song KY, Kim CS, Choi HS, Guo XH, Law PY, Wei LN, Loh HH.; ''Epigenetic programming of mu-opioid receptor gene in mouse brain is regulated by MeCP2 and Brg1 chromatin remodelling factor.''; PubMedEurope PMCScholia
Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M.; ''Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis.''; PubMedEurope PMCScholia
Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N, Mandel G.; ''A role for glia in the progression of Rett's syndrome.''; PubMedEurope PMCScholia
Le Y, Gao H, Bleday R, Zhu Z.; ''The homeobox protein VentX reverts immune suppression in the tumor microenvironment.''; PubMedEurope PMCScholia
Kadonaga JT.; ''Regulation of RNA polymerase II transcription by sequence-specific DNA binding factors.''; PubMedEurope PMCScholia
Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ, Jones JR, Scherer SW, Schanen NC, Friez MJ, Vincent JB, Minassian BA.; ''A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.''; PubMedEurope PMCScholia
Bäckström S, Wolf-Watz M, Grundström C, Härd T, Grundström T, Sauer UH.; ''The RUNX1 Runt domain at 1.25A resolution: a structural switch and specifically bound chloride ions modulate DNA binding.''; PubMedEurope PMCScholia
Dykes IM, Tempest L, Lee SI, Turner EE.; ''Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation.''; PubMedEurope PMCScholia
Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, David Sweatt J, Zoghbi HY.; ''Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.''; PubMedEurope PMCScholia
Zhang L, Lukasik SM, Speck NA, Bushweller JH.; ''Structural and functional characterization of Runx1, CBF beta, and CBF beta-SMMHC.''; PubMedEurope PMCScholia
Bamforth SD, Bragança J, Farthing CR, Schneider JE, Broadbent C, Michell AC, Clarke K, Neubauer S, Norris D, Brown NA, Anderson RH, Bhattacharya S.; ''Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway.''; PubMedEurope PMCScholia
Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, Kurokawa M.; ''A role for RUNX1 in hematopoiesis and myeloid leukemia.''; PubMedEurope PMCScholia
Teplyuk NM, Galindo M, Teplyuk VI, Pratap J, Young DW, Lapointe D, Javed A, Stein JL, Lian JB, Stein GS, van Wijnen AJ.; ''Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors.''; PubMedEurope PMCScholia
Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY.; ''MeCP2, a key contributor to neurological disease, activates and represses transcription.''; PubMedEurope PMCScholia
Begon DY, Delacroix L, Vernimmen D, Jackers P, Winkler R.; ''Yin Yang 1 cooperates with activator protein 2 to stimulate ERBB2 gene expression in mammary cancer cells.''; PubMedEurope PMCScholia
Rogers CD, Archer TC, Cunningham DD, Grammer TC, Casey EM.; ''Sox3 expression is maintained by FGF signaling and restricted to the neural plate by Vent proteins in the Xenopus embryo.''; PubMedEurope PMCScholia
Bragança J, Eloranta JJ, Bamforth SD, Ibbitt JC, Hurst HC, Bhattacharya S.; ''Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2.''; PubMedEurope PMCScholia
Trojer P, Cao AR, Gao Z, Li Y, Zhang J, Xu X, Li G, Losson R, Erdjument-Bromage H, Tempst P, Farnham PJ, Reinberg D.; ''L3MBTL2 protein acts in concert with PcG protein-mediated monoubiquitination of H2A to establish a repressive chromatin structure.''; PubMedEurope PMCScholia
Chen L, Chen K, Lavery LA, Baker SA, Shaw CA, Li W, Zoghbi HY.; ''MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome.''; PubMedEurope PMCScholia
Landry JR, Kinston S, Knezevic K, de Bruijn MF, Wilson N, Nottingham WT, Peitz M, Edenhofer F, Pimanda JE, Ottersbach K, Göttgens B.; ''Runx genes are direct targets of Scl/Tal1 in the yolk sac and fetal liver.''; PubMedEurope PMCScholia
Guy J, Gan J, Selfridge J, Cobb S, Bird A.; ''Reversal of neurological defects in a mouse model of Rett syndrome.''; PubMedEurope PMCScholia
Kelleher RJ, Flanagan PM, Kornberg RD.; ''A novel mediator between activator proteins and the RNA polymerase II transcription apparatus.''; PubMedEurope PMCScholia
Cartwright P, Müller H, Wagener C, Holm K, Helin K.; ''E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription.''; PubMedEurope PMCScholia
Trinh BQ, Barengo N, Kim SB, Lee JS, Zweidler-McKay PA, Naora H.; ''The homeobox gene DLX4 regulates erythro-megakaryocytic differentiation by stimulating IL-1β and NF-κB signaling.''; PubMedEurope PMCScholia
Lyst MJ, Ekiert R, Ebert DH, Merusi C, Nowak J, Selfridge J, Guy J, Kastan NR, Robinson ND, de Lima Alves F, Rappsilber J, Greenberg ME, Bird A.; ''Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor.''; PubMedEurope PMCScholia
Keita M, Bachvarova M, Morin C, Plante M, Gregoire J, Renaud MC, Sebastianelli A, Trinh XB, Bachvarov D.; ''The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion.''; PubMedEurope PMCScholia
Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K.; ''Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein.''; PubMedEurope PMCScholia
Pande S, Browne G, Padmanabhan S, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS.; ''Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.''; PubMedEurope PMCScholia
Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW.; ''The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation.''; PubMedEurope PMCScholia
Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA.; ''Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.''; PubMedEurope PMCScholia
Baron VT, Pio R, Jia Z, Mercola D.; ''Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer.''; PubMedEurope PMCScholia
Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, Steinhoff C, Schulz R, Lipkowitz B, Ropers HH, Holmes MC, Bird A.; ''Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome.''; PubMedEurope PMCScholia
Mellén M, Ayata P, Dewell S, Kriaucionis S, Heintz N.; ''MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system.''; PubMedEurope PMCScholia
Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K, Inoue K, Yamana K, Zanma A, Takada K, Ito Y, Komori T.; ''Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog.''; PubMedEurope PMCScholia
Wu X, Gao H, Ke W, Giese RW, Zhu Z.; ''The homeobox transcription factor VentX controls human macrophage terminal differentiation and proinflammatory activation.''; PubMedEurope PMCScholia
Justice NJ, Jan YN.; ''Variations on the Notch pathway in neural development.''; PubMedEurope PMCScholia
Kobayashi A, Senzaki K, Ozaki S, Yoshikawa M, Shiga T.; ''Runx1 promotes neuronal differentiation in dorsal root ganglion.''; PubMedEurope PMCScholia
Chen AI, de Nooij JC, Jessell TM.; ''Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord.''; PubMedEurope PMCScholia
Rawat VP, Arseni N, Ahmed F, Mulaw MA, Thoene S, Heilmeier B, Sadlon T, D'Andrea RJ, Hiddemann W, Bohlander SK, Buske C, Feuring-Buske M.; ''The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia.''; PubMedEurope PMCScholia
Tandon M, Chen Z, Pratap J.; ''Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells.''; PubMedEurope PMCScholia
Vladimirova V, Waha A, Lückerath K, Pesheva P, Probstmeier R.; ''Runx2 is expressed in human glioma cells and mediates the expression of galectin-3.''; PubMedEurope PMCScholia
Murakami M, Nakagawa M, Olson EN, Nakagawa O.; ''A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.''; PubMedEurope PMCScholia
Ruiz M, Pettaway C, Song R, Stoeltzing O, Ellis L, Bar-Eli M.; ''Activator protein 2alpha inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells.''; PubMedEurope PMCScholia
Ichikawa M, Asai T, Chiba S, Kurokawa M, Ogawa S.; ''Runx1/AML-1 ranks as a master regulator of adult hematopoiesis.''; PubMedEurope PMCScholia
Wong WF, Kohu K, Chiba T, Sato T, Satake M.; ''Interplay of transcription factors in T-cell differentiation and function: the role of Runx.''; PubMedEurope PMCScholia
Friedman AD.; ''Cell cycle and developmental control of hematopoiesis by Runx1.''; PubMedEurope PMCScholia
Zeng YX, Somasundaram K, el-Deiry WS.; ''AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression.''; PubMedEurope PMCScholia
Wu D, Ozaki T, Yoshihara Y, Kubo N, Nakagawara A.; ''Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation.''; PubMedEurope PMCScholia
Zhang HY, Jin L, Stilling GA, Ruebel KH, Coonse K, Tanizaki Y, Raz A, Lloyd RV.; ''RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors.''; PubMedEurope PMCScholia
Karsenty G, Olson EN.; ''Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication.''; PubMedEurope PMCScholia
Malik S, Roeder RG.; ''Dynamic regulation of pol II transcription by the mammalian Mediator complex.''; PubMedEurope PMCScholia
Giangrande PH, Zhu W, Schlisio S, Sun X, Mori S, Gaubatz S, Nevins JR.; ''A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription.''; PubMedEurope PMCScholia
Bragança J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S.; ''Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2.''; PubMedEurope PMCScholia
Gianakopoulos PJ, Zhang Y, Pencea N, Orlic-Milacic M, Mittal K, Windpassinger C, White SJ, Kroisel PM, Chow EW, Saunders CJ, Minassian BA, Vincent JB.; ''Mutations in MECP2 exon 1 in classical Rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2.''; PubMedEurope PMCScholia
Takeda S, Bonnamy JP, Owen MJ, Ducy P, Karsenty G.; ''Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice.''; PubMedEurope PMCScholia
Qiu Z, Sylwestrak EL, Lieberman DN, Zhang Y, Liu XY, Ghosh A.; ''The Rett syndrome protein MeCP2 regulates synaptic scaling.''; PubMedEurope PMCScholia
Huntley S, Baggott DM, Hamilton AT, Tran-Gyamfi M, Yang S, Kim J, Gordon L, Branscomb E, Stubbs L.; ''A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors.''; PubMedEurope PMCScholia
Gao H, Wu B, Le Y, Zhu Z.; ''Homeobox protein VentX induces p53-independent apoptosis in cancer cells.''; PubMedEurope PMCScholia
Boller S, Grosschedl R.; ''The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function.''; PubMedEurope PMCScholia
Bosher JM, Totty NF, Hsuan JJ, Williams T, Hurst HC.; ''A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma.''; PubMedEurope PMCScholia
Wolff EM, Liang G, Cortez CC, Tsai YC, Castelao JE, Cortessis VK, Tsao-Wei DD, Groshen S, Jones PA.; ''RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking.''; PubMedEurope PMCScholia
Eloranta JJ, Hurst HC.; ''Transcription factor AP-2 interacts with the SUMO-conjugating enzyme UBC9 and is sumolated in vivo.''; PubMedEurope PMCScholia
Luikenhuis S, Giacometti E, Beard CF, Jaenisch R.; ''Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice.''; PubMedEurope PMCScholia
Conaway JW, Florens L, Sato S, Tomomori-Sato C, Parmely TJ, Yao T, Swanson SK, Banks CA, Washburn MP, Conaway RC.; ''The mammalian Mediator complex.''; PubMedEurope PMCScholia
Nagarajan RP, Patzel KA, Martin M, Yasui DH, Swanberg SE, Hertz-Picciotto I, Hansen RL, Van de Water J, Pessah IN, Jiang R, Robinson WP, LaSalle JM.; ''MECP2 promoter methylation and X chromosome inactivation in autism.''; PubMedEurope PMCScholia
Johnson W, Albanese C, Handwerger S, Williams T, Pestell RG, Jameson JL.; ''Regulation of the human chorionic gonadotropin alpha- and beta-subunit promoters by AP-2.''; PubMedEurope PMCScholia
Li XQ, Lu JT, Tan CC, Wang QS, Feng YM.; ''RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization.''; PubMedEurope PMCScholia
Liyanage VR, Zachariah RM, Rastegar M.; ''Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells.''; PubMedEurope PMCScholia
Tahirov TH, Inoue-Bungo T, Morii H, Fujikawa A, Sasaki M, Kimura K, Shiina M, Sato K, Kumasaka T, Yamamoto M, Ishii S, Ogata K.; ''Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta.''; PubMedEurope PMCScholia
Williams CM, Scibetta AG, Friedrich JK, Canosa M, Berlato C, Moss CH, Hurst HC.; ''AP-2gamma promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene.''; PubMedEurope PMCScholia
Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G, Calcagno E, Morello N, Landsberger N, Biffo S, Pizzorusso T, Giustetto M, Broccoli V.; ''Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model.''; PubMedEurope PMCScholia
Wysokinski D, Blasiak J, Pawlowska E.; ''Role of RUNX2 in Breast Carcinogenesis.''; PubMedEurope PMCScholia
Nakamura S, Senzaki K, Yoshikawa M, Nishimura M, Inoue K, Ito Y, Ozaki S, Shiga T.; ''Dynamic regulation of the expression of neurotrophin receptors by Runx3.''; PubMedEurope PMCScholia
Kerr B, Soto C J, Saez M, Abrams A, Walz K, Young JI.; ''Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes.''; PubMedEurope PMCScholia
Goldfarb AN.; ''Megakaryocytic programming by a transcriptional regulatory loop: A circle connecting RUNX1, GATA-1, and P-TEFb.''; PubMedEurope PMCScholia
Moretti PA, Davidson AJ, Baker E, Lilley B, Zon LI, D'Andrea RJ.; ''Molecular cloning of a human Vent-like homeobox gene.''; PubMedEurope PMCScholia
Drissi H, Luc Q, Shakoori R, Chuva De Sousa Lopes S, Choi JY, Terry A, Hu M, Jones S, Neil JC, Lian JB, Stein JL, Van Wijnen AJ, Stein GS.; ''Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene.''; PubMedEurope PMCScholia
Kriaucionis S, Bird A.; ''The major form of MeCP2 has a novel N-terminus generated by alternative splicing.''; PubMedEurope PMCScholia
Freedman LP.; ''Multimeric Coactivator Complexes for Steroid/Nuclear Receptors.''; PubMedEurope PMCScholia
Sato M, Morii E, Komori T, Kawahata H, Sugimoto M, Terai K, Shimizu H, Yasui T, Ogihara H, Yasui N, Ochi T, Kitamura Y, Ito Y, Nomura S.; ''Transcriptional regulation of osteopontin gene in vivo by PEBP2alphaA/CBFA1 and ETS1 in the skeletal tissues.''; PubMedEurope PMCScholia
Li H, Zhong X, Chau KF, Santistevan NJ, Guo W, Kong G, Li X, Kadakia M, Masliah J, Chi J, Jin P, Zhang J, Zhao X, Chang Q.; ''Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signalling pathway.''; PubMedEurope PMCScholia
Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K, Zechner U, Ludwig L, Wilda M, Hameister H, Knöchel W, Liptay S, Schmid RM.; ''SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway.''; PubMedEurope PMCScholia
The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.
The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
Summary: ARC co-activator complex and assembly The ARC coactivator complex is a subset of 19 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes (Figure 1). Adapter complexes bridge between the basal transcription factors (including Pol II) and tisue-specific transcrption factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001). The ARC complex contains the 15 components present in the DRIP complex, as well as 4 additional components (Rachez, 1999), These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004). The 15 ARC complex components that are shared with the DRIP complex components, are also shared with the TRAP coactivator complex. However, the TRAP complex also has 4 additional, distinct components (Bourbon, 2004), which are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme. The ARC complex was originally identified and named as a co-activator complex associated with transcription activator proteins (reviewed in Malik, 2005 and references therein). It was subsequently determined that all of the components of the DRIP complex are also in the ARC complex, and in the TRAP complex. In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004). The order of addition of the ARC proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, ARC complex assembly is represented as a single reaction, in which all 19 components assemble simultaneously into the ARC co-activator complex.
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
The proteins listed here have been divided into two groups based on the amount of data from direct experimental assy or detailed sequence analysis that is available to assign a receptor function to each. Those backed by more evidence have "member" status; ones backed by less have "candidate" status.
The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.
The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).
In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009).
YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010).
The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.
The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).
The TRAP co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations and in different contexts, form specific co-activator or "Adapter" complexes in human cells. These complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The TRAP complex was originally identified and named as a co-activator complex associated with the Thyroid Hormone Receptor member of the nuclear receptor family of transcription factors (Yuan, 1998). It was later determined that many of the components of the TRAP complex are also in the DRIP complex, and in the ARC complex.
The TRAP complex contains the following 14 proteins, which also are common to the DRIP and ARC complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
The TRAP complex also contains 4 additional components, which are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme (Bourbon, 2004).
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).
The order of addition of the TRAP proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, TRAP co-activator complex assembly is represented as a single reaction event, in which all 18 components assemble simultaneously into the TRAP co-activator complex.
The ARC co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes in human cells. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The ARC complex was originally identified and named as a co-activator complex associated with transcription activator proteins (reviewed in Malik, 2005 and references therein). It was subsequently determined that many of the components of the ARC complex are also in the DRIP complex, and in the TRAP complex..
The ARC complex contains the following 14 proteins, which also are common to the DRIP and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
The ARC complex also contains 4 additional, ARC-specific components, which are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).
The order of addition of the ARC proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, ARC complex assembly is represented as a single reaction event, in which all 19 components assemble simultaneously into the ARC co-activator complex.
Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004).
THE NUCLEAR RECEPTOR-MED1 REACTION: The Nuclear Receptor (NR) proteins are a highly conserved family of DNA-binding transcription factors that bind certain hormones, vitamins, and other small, diffusible signaling molecules. The non-liganded NRs recruit specific corepressor complexes of the NCOR/SMRT type, to mediate transcriptional repression of the target genes to which they are bound. During signaling, ligand binding to a specific domain in the NR proteins induces a conformational change that results in the exchange of the associated corepressor complex, and its replacement by a specific coactivator complex of either the TRAP/DRIP/Mediator type, or the p160/SRC type. The Mediator coactivator complexes typically nucleate around the MED1 coactivator protein, which is directly bound to the NR transcription factor (reviewed in Freedman, 1999; Malik, 2005).
A general feature of the NR proteins is that they each contain a specific protein interaction domain (PID), or domains, that mediates the specific binding interactions with the MED1 proteins. In the ligand-bound state, NRs each take part in an NR-MED1 binding reaction to form an NR-MED1 complex. The bound MED1 then functions to nucleate the assembly of additional specific coactivator proteins, depending on the cell and DNA context, such as what specific target gene promoter or enhancer they are bound to, and in what cell type.
The formation of specific MED1-containing coactivator complexes on specific NR proteins has been well-characterized for a number of the human NR proteins. For example, binding of Vitamin D to the human Vitamin D3 Receptor was found to result in the recruitment of a specific complex of D Receptor Interacting Proteins - the DRIP coactivator complex (Rachez, 1998). Within the DRIP complex, the DRIP205 subunit was later renamed human "MED1", based on sequence similarities with yeast MED1 (reviewed in Bourbon, 2004).
Similarly, binding of thyroid hormone (TH) to the human TH Receptor (THRA or THRB) was found to result in the recruitment of a specific complex of Thyroid Receptor Associated Proteins - the TRAP coactivator complex (Yuan, 1998). The TRAP220 subunit was later identified to be the Mediator 1 (MED1) homologue (summarized in Bourbon, et al., 2004; Table 1).
The 48 human NR proteins each contain the PID(s) known to mediate interaction with the human MED1 protein. Direct NR-MED1 protein-protein interactions have been shown for a number of the NR proteins. The MED1-interacting PIDs are conserved in all of the human NRs. Therefore, each of the human NRs is known or expected to interact with MED1 in the appropriate cell context, depending on the cell type, the cell state, and the target gene regulatory region involved.
Formation of the KRAB ZNF / KAP1 Corepressor Complex:
Transcription factors which contain tandem copies of the C2H2 zinc finger DNA binding motif (ZNFs) are the most abundant class of TFs in the human proteome, comprising more than 1000 members. The KRAB ZNF proteins are the largest subset of these (with 423 members) and are defined by having an additional conserved domain, the KRAB domain (Bellefroid,1991, Margolin, 1994, Urrutia, 2003, Huntley, 2006). The Kruppel Associated Box (KRAB) domain is a transcription repression domain (Margolin, 1994) which mediates the recruitment of a specific and dedicated co repressor protein for the KRAB-ZNF family - KAP1 - which is required for transcriptional repression and gene silencing (Friedman, 1996).
The larger family of ZNF transcription factors are present in almost all metazoans and generally their DNA binding specificities and transcription regulation functions are conserved from Drosophila to humans. Although the biological functions of most ZNF TFs is not known, they often function biochemically as sequence specific DNA binding proteins and can be activators, or more oftenly observed, repressors of transcription, depending on cellular context. Transcriptional repression is mediated via specific protein protein interaction surfaces in the ZNF that function as repression domains, by recruiting specific co repressors, such as KAP1 in humans (Friedman, 1996), and dCTBP in Drosophila (Nibu, 1998).
In contrast to the larger ZNF family, the KRAB-ZNFs only appear much later in vertebrate evolution: genes encoding the primordial KRAB ZNF subfamily first arose in tetrapods and the family has been greatly expanded in numbers and complexity in mammals. Interestingly,a large fraction of KRAB-ZNFs are found only in primates. In addition to their rapid and dynamic evolutionary history, comparative genomics and expression studies of primate KRAB-ZNFs suggest that these genes have played a significant role in shaping primate specific traits (Huntley, 2006, Nowick, 2009).
The biochemical pathway utilized by KRAB-ZNFs is well defined and probably nearly identical for each member: All KRAB-ZNF proteins which have been studied in detail are repressors and utilize the KRAB domain to bind the KAP1 co-repressor. This interaction is direct, of high affinity, and is obligate for the KRAB-ZNF to function as a repressor when bound to DNA in vivo (Peng, 2000a,b).. The KAP1co-repressor appears to function as a scaffold protein to assemble and coordinate multiple enzymes (histone de-acetylases, histone methyltransferases and heterochromatin proteins) which target and modify chromatin structure thus leading to a compacted, silent state (Lechner, 2000; Schultz, 2001 Schultz, 2002 , Ayyanathan, 2003). The post-translational modification of KAP1 by SUMO controls its ability to assemble the enzymatic apparatus in chromatin (Ivanov, 2007; Zeng, 2008). It is formally possible that some KRAB ZNF proteins may have additional functional domains that recruit coactivators in specific contexts, given that such bifunctionality is common for many classes of DNA binding transcription factors,. However, there is no experimental evidence for this yet.
There also is good evidence that the KRAB ZNF-KAP1 complex proteins can have long range gene silencing functions, by nucleating chromatin complexes that inactivate transcription of large numbers of genes over large distances by assembling silent heterochromatin (Ayyanathan, 2003). Although KAP1 was originally identified as a mediator of specific gene transcription repression, subsequent studies have shown that KAP1 also is involved in the recruitment of homologues of the HP1 protein family (Ryan, 1999, Ayyanathan, 2003; Lechner, 2000). These nonhistone heterochromatin associated proteins were first shown to have an epigenetic gene silencing function in Drosophila and more recently in mammalian cells . These studies suggest that KRAB ZNF proteins and KAP1 may also be involved in large scale chromatin regulation and gene silencing, not just in gene specific transcriptional repression. Whether this is a general property of most or all KRAB ZNF proteins will require additional studies.
Finally, several KRAB containing ZNFs in mammals also contain a conserved SCAN domain which, like the KRAB domain also functions as a protein protein interaction domain. (Edelstein, 2005, Peng, 2000a,b). The SCAN domain does not participate in KAP1 binding but rather functions to mediate homodimerization, or selective heterodimerization with other SCAN containing proteins. However, the biochemical and biological functions of the SCAN domain in KRAB-ZNF mediated repression are not known.
Remaining Questions: The single most important unanswered question for KRAB-ZNFDs is to determine their biological functions. While the mechanism utilized by the KRAB ZNF / KAP1 protein complex to mediate gene specific transcription repression is well understood , much less known about the specific biological pathways they control. Preliminary evidence from recent whole genome analysis of the target genes for the KRAB- ZNF263 protein suggest that it can have both positive and negative effects on transcriptional regulation of its target genes (Frietze, 2010). Presumably, each KRAB-ZNF, via its array of zinc fingers can bind to specific DNA recognition sequences in target promoters. This, combined with highly tissue specific expression of each gene, makes the potential transcriptome controlled by the 423 KRAB-ZNFs extremely large.
Detailed studies of gene transcription regulation in a wide variety of eukaryotic systems has revealed the general principles and mechanisms by which cell- or tissue-specific regulation of differential gene transcription is mediated (reviewed in Naar, 2001. Kadonaga, 2004, Maston, 2006, Barolo, 2002; Roeder, 2005, Rosenfeld, 2006). Of the three major classes of DNA polymerase involved in eukaryotic gene transcription, Polymerase II generally regulates protein-encoding genes. Figure 1 shows a diagram of the various components involved in cell-specific regulation of Pol-II gene transcription.
Core Promoter: Pol II-regulated genes typically have a Core Promoter where Pol II and a variety of general factors bind to specific DNA motifs:
i: the TATA box (TATA DNA sequence), which is bound by the "TATA-binding protein" (TBP).
ii: the Initiator motif (INR), where Pol II and certain other core factors bind, is present in many Pol II-regulated genes.
iii: the Downstream Promoter Element (DPE), which is present in a subset of Pol II genes, and where additional core factors bind.
The core promoter binding factors are generally ubiquitously expressed, although there are exceptions to this.
Proximal Promoter: immediately upstream (5') of the core promoter, Pol II target genes often have a Proximal Promoter region that spans up to 500 base pairs (b.p.), or even to 1000 b.p.. This region contains a number of functional DNA binding sites for a specific set of transcription activator (TA) and transcription repressor (TR) proteins. These TA and TR factors are generally cell- or tissue-specific in expression, rather than ubiquitous, so that the presence of their cognate binding sites in the proximal promoter region programs cell- or tissue-specific expression of the target gene, perhaps in conjunction with TA and TR complexes bound in distal enhancer regions.
Distal Enhancer(s): many or most Pol II regulated genes in higher eukaryotes have one or more distal Enhancer regions which are essential for proper regulation of the gene, often in a cell or tissue-specific pattern. Like the proximal promoter region, each of the distal enhancer regions typically contain a cluster of binding sites for specific TA and/or TR DNA-binding factors, rather than just a single site.
Enhancers generally have three defining characteristics:
i: They can be located very long distances from the promoter of the target gene they regulate, sometimes as far as 100 Kb, or more.
ii: They can be either upstream (5') or downstream (3') of the target gene, including within introns of that gene.
iii: They can function in either orientation in the DNA.
Combinatorial mechanisms of transcription regulation: The specific combination of TA and TR binding sites within the proximal promoter and/or distal enhancer(s) provides a "combinatorial transcription code" that mediates cell- or tissue-specific expression of the associated target gene. Each promoter or enhancer region mediates expression in a specific subset of the overall expression pattern. In at least some cases, each enhancer region functions completely independently of the others, so that the overall expression pattern is a linear combination of the expression patterns of each of the enhancer modules.
Co-Activator and Co-Repressor Complexes: DNA-bound TA and TR proteins typically recruit the assembly of specific Co-Activator (Co-A) and Co-Repressor (Co-R) Complexes, respectively, which are essential for regulating target gene transcription. Both Co-A's and Co-R's are multi-protein complexes that contain several specific protein components.
Co-Activator complexes generally contain at lease one component protein that has Histone Acetyl Transferase (HAT) enzymatic activity. This functions to acetylate Histones and/or other chromatin-associated factors, which typically increases that transcription activation of the target gene. By contrast, Co-Repressor complexes generally contain at lease one component protein that has Histone De-Acetylase (HDAC) enzymatic activity. This functions to de-acetylate Histones and/or other chromatin-associated factors. This typically increases the transcription repression of the target gene.
Adaptor (Mediator) complexes: In addition to the co-activator complexes that assemble on particular cell-specific TA factors, - there are at least two additional transcriptional co-activator complexes common to most cells. One of these is the Mediator complex, which functions as an "adaptor" complex that bridges between the tissue-specific co-activator complexes assembled in the proximal promoter (or distal enhancers). The human Mediator complex has been shown to contain at least 19 protein distinct components. Different combinations of these co-activator proteins are also found to be components of specific transcription Co-Activator complexes, such as the DRIP, TRAP and ARC complexes described below.
TBP/TAF complex: Another large Co-A complex is the "TBP-associated factors" (TAFs) that assemble on TBP (TATA-Binding Protein), which is bound to the TATA box present in many promoters. There are at least 23 human TAF proteins that have been identified. Many of these are ubiquitously expressed, but TAFs can also be expressed in a cell or tissue-specific pattern.
Specific Coactivator Complexes for DNA-binding Transcription Factors.
A number of specific co-activator complexes for DNA-binding transcription factors have been identified, including DRIP, TRAP, and ARC (reviewed in Bourbon, 2004, Blazek, 2005, Conaway, 2005, and Malik, 2005). The DRIP co-activator complex was originally identified and named as a specific complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). Similarly, the TRAP co-activator complex was originally identified as a complex that associates with the thyroid receptor (Yuan, 1998). It was later determined that all of the components of the DRIP complex are also present in the TRAP complex, and the ARC complex (discussed further below). For example, the DRIP205 and TRAP220 proteins were show to be identical, as were specific pairs of the other components of these complexes (Rachez, 1999).
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator ("adaptor") complex proteins (reviewed in Bourbon, 2004). The Mediator proteins were originally identified in yeast by Kornberg and colleagues, as complexes associated with DNA polymerase (Kelleher, 1990). In higher organisms, Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (Figure 1). However, many of the Mediator homologues can also be found in complexes associated with specific transcription factors in higher organisms. A unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004). For example, the DRIP205 / TRAP220 proteins are now identified as Mediator 1 (Rachez, 1999), based on homology with yeast Mediator 1.
Example Pathway: Specific Regulation of Target Genes During Notch Signaling:
One well-studied example of cell-specific regulation of gene transcription is selective regulation of target genes during Notch signaling. Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL.
In Drosophila, Su(H) is known to be bifunctional, in that it represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.
Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).
In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila.
During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus (Figure 2). Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-R complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002).
Thus, CSL is a good example of a bifunctional DNA-binding transcription factor that mediates repression of specific targets genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling.
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The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.
The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).
The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.
The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).
Annotated Interactions
The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.
The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).
The TRAP co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations and in different contexts, form specific co-activator or "Adapter" complexes in human cells. These complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The TRAP complex was originally identified and named as a co-activator complex associated with the Thyroid Hormone Receptor member of the nuclear receptor family of transcription factors (Yuan, 1998). It was later determined that many of the components of the TRAP complex are also in the DRIP complex, and in the ARC complex.
The TRAP complex contains the following 14 proteins, which also are common to the DRIP and ARC complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
The TRAP complex also contains 4 additional components, which are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme (Bourbon, 2004).
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).
The order of addition of the TRAP proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, TRAP co-activator complex assembly is represented as a single reaction event, in which all 18 components assemble simultaneously into the TRAP co-activator complex.
The ARC co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes in human cells. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).
The ARC complex was originally identified and named as a co-activator complex associated with transcription activator proteins (reviewed in Malik, 2005 and references therein). It was subsequently determined that many of the components of the ARC complex are also in the DRIP complex, and in the TRAP complex..
The ARC complex contains the following 14 proteins, which also are common to the DRIP and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.
The ARC complex also contains 4 additional, ARC-specific components, which are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).
In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).
The order of addition of the ARC proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, ARC complex assembly is represented as a single reaction event, in which all 19 components assemble simultaneously into the ARC co-activator complex.
A general feature of the NR proteins is that they each contain a specific protein interaction domain (PID), or domains, that mediates the specific binding interactions with the MED1 proteins. In the ligand-bound state, NRs each take part in an NR-MED1 binding reaction to form an NR-MED1 complex. The bound MED1 then functions to nucleate the assembly of additional specific coactivator proteins, depending on the cell and DNA context, such as what specific target gene promoter or enhancer they are bound to, and in what cell type.
The formation of specific MED1-containing coactivator complexes on specific NR proteins has been well-characterized for a number of the human NR proteins. For example, binding of Vitamin D to the human Vitamin D3 Receptor was found to result in the recruitment of a specific complex of D Receptor Interacting Proteins - the DRIP coactivator complex (Rachez, 1998). Within the DRIP complex, the DRIP205 subunit was later renamed human "MED1", based on sequence similarities with yeast MED1 (reviewed in Bourbon, 2004).
Similarly, binding of thyroid hormone (TH) to the human TH Receptor (THRA or THRB) was found to result in the recruitment of a specific complex of Thyroid Receptor Associated Proteins - the TRAP coactivator complex (Yuan, 1998). The TRAP220 subunit was later identified to be the Mediator 1 (MED1) homologue (summarized in Bourbon, et al., 2004; Table 1).
The 48 human NR proteins each contain the PID(s) known to mediate interaction with the human MED1 protein. Direct NR-MED1 protein-protein interactions have been shown for a number of the NR proteins. The MED1-interacting PIDs are conserved in all of the human NRs. Therefore, each of the human NRs is known or expected to interact with MED1 in the appropriate cell context, depending on the cell type, the cell state, and the target gene regulatory region involved.Formation of the KRAB ZNF / KAP1 Corepressor Complex:
Transcription factors which contain tandem copies of the C2H2 zinc finger DNA binding motif (ZNFs) are the most abundant class of TFs in the human proteome, comprising more than 1000 members. The KRAB ZNF proteins are the largest subset of these (with 423 members) and are defined by having an additional conserved domain, the KRAB domain (Bellefroid,1991, Margolin, 1994, Urrutia, 2003, Huntley, 2006). The Kruppel Associated Box (KRAB) domain is a transcription repression domain (Margolin, 1994) which mediates the recruitment of a specific and dedicated co repressor protein for the KRAB-ZNF family - KAP1 - which is required for transcriptional repression and gene silencing (Friedman, 1996).
The larger family of ZNF transcription factors are present in almost all metazoans and generally their DNA binding specificities and transcription regulation functions are conserved from Drosophila to humans. Although the biological functions of most ZNF TFs is not known, they often function biochemically as sequence specific DNA binding proteins and can be activators, or more oftenly observed, repressors of transcription, depending on cellular context. Transcriptional repression is mediated via specific protein protein interaction surfaces in the ZNF that function as repression domains, by recruiting specific co repressors, such as KAP1 in humans (Friedman, 1996), and dCTBP in Drosophila (Nibu, 1998).
In contrast to the larger ZNF family, the KRAB-ZNFs only appear much later in vertebrate evolution: genes encoding the primordial KRAB ZNF subfamily first arose in tetrapods and the family has been greatly expanded in numbers and complexity in mammals. Interestingly,a large fraction of KRAB-ZNFs are found only in primates. In addition to their rapid and dynamic evolutionary history, comparative genomics and expression studies of primate KRAB-ZNFs suggest that these genes have played a significant role in shaping primate specific traits (Huntley, 2006, Nowick, 2009).
The biochemical pathway utilized by KRAB-ZNFs is well defined and probably nearly identical for each member: All KRAB-ZNF proteins which have been studied in detail are repressors and utilize the KRAB domain to bind the KAP1 co-repressor. This interaction is direct, of high affinity, and is obligate for the KRAB-ZNF to function as a repressor when bound to DNA in vivo (Peng, 2000a,b).. The KAP1co-repressor appears to function as a scaffold protein to assemble and coordinate multiple enzymes (histone de-acetylases, histone methyltransferases and heterochromatin proteins) which target and modify chromatin structure thus leading to a compacted, silent state (Lechner, 2000; Schultz, 2001 Schultz, 2002 , Ayyanathan, 2003). The post-translational modification of KAP1 by SUMO controls its ability to assemble the enzymatic apparatus in chromatin (Ivanov, 2007; Zeng, 2008). It is formally possible that some KRAB ZNF proteins may have additional functional domains that recruit coactivators in specific contexts, given that such bifunctionality is common for many classes of DNA binding transcription factors,. However, there is no experimental evidence for this yet.
There also is good evidence that the KRAB ZNF-KAP1 complex proteins can have long range gene silencing functions, by nucleating chromatin complexes that inactivate transcription of large numbers of genes over large distances by assembling silent heterochromatin (Ayyanathan, 2003). Although KAP1 was originally identified as a mediator of specific gene transcription repression, subsequent studies have shown that KAP1 also is involved in the recruitment of homologues of the HP1 protein family (Ryan, 1999, Ayyanathan, 2003; Lechner, 2000). These nonhistone heterochromatin associated proteins were first shown to have an epigenetic gene silencing function in Drosophila and more recently in mammalian cells . These studies suggest that KRAB ZNF proteins and KAP1 may also be involved in large scale chromatin regulation and gene silencing, not just in gene specific transcriptional repression. Whether this is a general property of most or all KRAB ZNF proteins will require additional studies.
Finally, several KRAB containing ZNFs in mammals also contain a conserved SCAN domain which, like the KRAB domain also functions as a protein protein interaction domain. (Edelstein, 2005, Peng, 2000a,b). The SCAN domain does not participate in KAP1 binding but rather functions to mediate homodimerization, or selective heterodimerization with other SCAN containing proteins. However, the biochemical and biological functions of the SCAN domain in KRAB-ZNF mediated repression are not known.
Remaining Questions: The single most important unanswered question for KRAB-ZNFDs is to determine their biological functions. While the mechanism utilized by the KRAB ZNF / KAP1 protein complex to mediate gene specific transcription repression is well understood , much less known about the specific biological pathways they control. Preliminary evidence from recent whole genome analysis of the target genes for the KRAB- ZNF263 protein suggest that it can have both positive and negative effects on transcriptional regulation of its target genes (Frietze, 2010). Presumably, each KRAB-ZNF, via its array of zinc fingers can bind to specific DNA recognition sequences in target promoters. This, combined with highly tissue specific expression of each gene, makes the potential transcriptome controlled by the 423 KRAB-ZNFs extremely large.