Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong MQ, Frangou CG, Yates JR, Wright PE, Han J.; ''PRAK is essential for ras-induced senescence and tumor suppression.''; 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
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y.; ''Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.''; PubMedEurope PMCScholia
Derry JJ, Richard S, Valderrama Carvajal H, Ye X, Vasioukhin V, Cochrane AW, Chen T, Tyner AL.; ''Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability.''; PubMedEurope PMCScholia
Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.; ''Molecular interpretation of ERK signal duration by immediate early gene products.''; PubMedEurope PMCScholia
Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMedEurope PMCScholia
Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G, Gil J.; ''Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.''; PubMedEurope PMCScholia
Watanabe N, Broome M, Hunter T.; ''Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle.''; PubMedEurope PMCScholia
New L, Jiang Y, Han J.; ''Regulation of PRAK subcellular location by p38 MAP kinases.''; PubMedEurope PMCScholia
Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMedEurope PMCScholia
Glover JN, Harrison SC.; ''Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA.''; PubMedEurope PMCScholia
Borriello A, Caldarelli I, Bencivenga D, Cucciolla V, Oliva A, Usala E, Danise P, Ronzoni L, Perrotta S, Della Ragione F.; ''p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells.''; PubMedEurope PMCScholia
Baek KH, Ryeom S.; ''Detection of Oncogene-Induced Senescence In Vivo.''; PubMedEurope PMCScholia
Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP.; ''Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase.''; PubMedEurope PMCScholia
Zacksenhaus E, Bremner R, Phillips RA, Gallie BL.; ''A bipartite nuclear localization signal in the retinoblastoma gene product and its importance for biological activity.''; PubMedEurope PMCScholia
Blain SW, Montalvo E, Massagué J.; ''Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4.''; PubMedEurope PMCScholia
Bisteau X, Paternot S, Colleoni B, Ecker K, Coulonval K, De Groote P, Declercq W, Hengst L, Roger PP.; ''CDK4 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK4/CDK2 interplay mediated by p21 phosphorylation at the restriction point.''; PubMedEurope PMCScholia
Cerqueira A, Martín A, Symonds CE, Odajima J, Dubus P, Barbacid M, Santamaría D.; ''Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors.''; PubMedEurope PMCScholia
Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.''; PubMedEurope PMCScholia
Sherr CJ, Roberts JM.; ''CDK inhibitors: positive and negative regulators of G1-phase progression.''; PubMedEurope PMCScholia
Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J.; ''Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network.''; PubMedEurope PMCScholia
Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMedEurope PMCScholia
Zou L, Stillman B.; ''Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase.''; PubMedEurope PMCScholia
Zhang Y, Xiong Y, Yarbrough WG.; ''ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.''; PubMedEurope PMCScholia
Ikeda O, Miyasaka Y, Sekine Y, Mizushima A, Muromoto R, Nanbo A, Yoshimura A, Matsuda T.; ''STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation.''; PubMedEurope PMCScholia
Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK.; ''E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1).''; PubMedEurope PMCScholia
Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A.; ''Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.''; PubMedEurope PMCScholia
Dou QP, Zhao S, Levin AH, Wang J, Helin K, Pardee AB.; ''G1/S-regulated E2F-containing protein complexes bind to the mouse thymidine kinase gene promoter.''; PubMedEurope PMCScholia
Bockstaele L, Coulonval K, Kooken H, Paternot S, Roger PP.; ''Regulation of CDK4.''; PubMedEurope PMCScholia
Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M.; ''Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.''; PubMedEurope PMCScholia
Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d'Adda di Fagagna F, Bernard D, Hernando E, Gil J.; ''Chemokine signaling via the CXCR2 receptor reinforces senescence.''; PubMedEurope PMCScholia
Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW.; ''Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.''; PubMedEurope PMCScholia
Takahashi A, Imai Y, Yamakoshi K, Kuninaka S, Ohtani N, Yoshimoto S, Hori S, Tachibana M, Anderton E, Takeuchi T, Shinkai Y, Peters G, Saya H, Hara E.; ''DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells.''; PubMedEurope PMCScholia
Lindeman GJ, Gaubatz S, Livingston DM, Ginsberg D.; ''The subcellular localization of E2F-4 is cell-cycle dependent.''; PubMedEurope PMCScholia
Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M.; ''Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth.''; PubMedEurope PMCScholia
Lukong KE, Huot ME, Richard S.; ''BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest.''; PubMedEurope PMCScholia
Hansen K, Farkas T, Lukas J, Holm K, Rönnstrand L, Bartek J.; ''Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block.''; PubMedEurope PMCScholia
Jimi E, Ikebe T, Takahashi N, Hirata M, Suda T, Koga T.; ''Interleukin-1 alpha activates an NF-kappaB-like factor in osteoclast-like cells.''; PubMedEurope PMCScholia
Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH.; ''Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion.''; PubMedEurope PMCScholia
Rayman JB, Takahashi Y, Indjeian VB, Dannenberg JH, Catchpole S, Watson RJ, te Riele H, Dynlacht BD.; ''E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex.''; PubMedEurope PMCScholia
Magenta A, Fasanaro P, Romani S, Di Stefano V, Capogrossi MC, Martelli F.; ''Protein phosphatase 2A subunit PR70 interacts with pRb and mediates its dephosphorylation.''; PubMedEurope PMCScholia
Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMedEurope PMCScholia
Chittenden T, Livingston DM, Kaelin WG.; ''The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein.''; PubMedEurope PMCScholia
Coulonval K, Bockstaele L, Paternot S, Dumont JE, Roger PP.; ''The cyclin D3-CDK4-p27kip1 holoenzyme in thyroid epithelial cells: activation by TSH, inhibition by TGFbeta, and phosphorylations of its subunits demonstrated by two-dimensional gel electrophoresis.''; PubMedEurope PMCScholia
Chung M, Liu C, Yang HW, Köberlin MS, Cappell SD, Meyer T.; ''Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1.''; PubMedEurope PMCScholia
Ostrander JH, Daniel AR, Lofgren K, Kleer CG, Lange CA.; ''Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells.''; PubMedEurope PMCScholia
Yang BS, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC.; ''Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.''; PubMedEurope PMCScholia
Bagui TK, Mohapatra S, Haura E, Pledger WJ.; ''P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes.''; PubMedEurope PMCScholia
Schachter MM, Merrick KA, Larochelle S, Hirschi A, Zhang C, Shokat KM, Rubin SM, Fisher RP.; ''A Cdk7-Cdk4 T-loop phosphorylation cascade promotes G1 progression.''; PubMedEurope PMCScholia
Zhu XH, Nguyen H, Halicka HD, Traganos F, Koff A.; ''Noncatalytic requirement for cyclin A-cdk2 in p27 turnover.''; PubMedEurope PMCScholia
Gambus A, van Deursen F, Polychronopoulos D, Foltman M, Jones RC, Edmondson RD, Calzada A, Labib K.; ''A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryotic replisome.''; PubMedEurope PMCScholia
Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, Williams RS.; ''Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.''; PubMedEurope PMCScholia
Yoshida K, Inoue I.; ''Regulation of Geminin and Cdt1 expression by E2F transcription factors.''; PubMedEurope PMCScholia
Meng W, Swenson LL, Fitzgibbon MJ, Hayakawa K, Ter Haar E, Behrens AE, Fulghum JR, Lippke JA.; ''Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export.''; PubMedEurope PMCScholia
Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC.; ''Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.''; PubMedEurope PMCScholia
Ezhevsky SA, Ho A, Becker-Hapak M, Davis PK, Dowdy SF.; ''Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo.''; PubMedEurope PMCScholia
Shin I, Rotty J, Wu FY, Arteaga CL.; ''Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry.''; PubMedEurope PMCScholia
Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M.; ''Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.''; PubMedEurope PMCScholia
Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ.; ''MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.''; PubMedEurope PMCScholia
Darbinian N, Gallia GL, Kundu M, Shcherbik N, Tretiakova A, Giordano A, Khalili K.; ''Association of Pur alpha and E2F-1 suppresses transcriptional activity of E2F-1.''; PubMedEurope PMCScholia
Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA.; ''Regulated association of protein kinase B/Akt with breast tumor kinase.''; PubMedEurope PMCScholia
Kamalati T, Jolin HE, Fry MJ, Crompton MR.; ''Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation.''; PubMedEurope PMCScholia
Blomberg I, Hoffmann I.; ''Ectopic expression of Cdc25A accelerates the G(1)/S transition and leads to premature activation of cyclin E- and cyclin A-dependent kinases.''; PubMedEurope PMCScholia
Jiang W, McDonald D, Hope TJ, Hunter T.; ''Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication.''; PubMedEurope PMCScholia
Woo MS, Sánchez I, Dynlacht BD.; ''p130 and p107 use a conserved domain to inhibit cellular cyclin-dependent kinase activity.''; PubMedEurope PMCScholia
Erickson S, Sangfelt O, Heyman M, Castro J, Einhorn S, Grandér D.; ''Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence.''; PubMedEurope PMCScholia
Pires IM, Blokland NJ, Broos AW, Poujade FA, Senra JM, Eccles SA, Span PN, Harvey AJ, Hammond EM.; ''HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion.''; PubMedEurope PMCScholia
Fleming Y, Armstrong CG, Morrice N, Paterson A, Goedert M, Cohen P.; ''Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7.''; PubMedEurope PMCScholia
LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E.; ''New functional activities for the p21 family of CDK inhibitors.''; PubMedEurope PMCScholia
Giangrande PH, Zhu W, Rempel RE, Laakso N, Nevins JR.; ''Combinatorial gene control involving E2F and E Box family members.''; PubMedEurope PMCScholia
Larrea MD, Liang J, Da Silva T, Hong F, Shao SH, Han K, Dumont D, Slingerland JM.; ''Phosphorylation of p27Kip1 regulates assembly and activation of cyclin D1-Cdk4.''; PubMedEurope PMCScholia
Meyerson M, Harlow E.; ''Identification of G1 kinase activity for cdk6, a novel cyclin D partner.''; PubMedEurope PMCScholia
Kang SA, Lee ST.; ''PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation.''; PubMedEurope PMCScholia
Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMedEurope PMCScholia
Sugimoto M, Martin N, Wilks DP, Tamai K, Huot TJ, Pantoja C, Okumura K, Serrano M, Hara E.; ''Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).''; PubMedEurope PMCScholia
Wotton D, Lo RS, Lee S, Massagué J.; ''A Smad transcriptional corepressor.''; PubMedEurope PMCScholia
Asano M, Wharton RP.; ''E2F mediates developmental and cell cycle regulation of ORC1 in Drosophila.''; PubMedEurope PMCScholia
Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMedEurope PMCScholia
Jackman M, Kubota Y, den Elzen N, Hagting A, Pines J.; ''Cyclin A- and cyclin E-Cdk complexes shuttle between the nucleus and the cytoplasm.''; 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
Ohtani K, Nevins JR.; ''Functional properties of a Drosophila homolog of the E2F1 gene.''; PubMedEurope PMCScholia
To KH, Pajovic S, Gallie BL, Thériault BL.; ''Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development.''; PubMedEurope PMCScholia
Ray A, James MK, Larochelle S, Fisher RP, Blain SW.; ''p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes.''; PubMedEurope PMCScholia
Lin TY, Cheng YC, Yang HC, Lin WC, Wang CC, Lai PL, Shieh SY.; ''Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis.''; PubMedEurope PMCScholia
White A, Pargellis CA, Studts JM, Werneburg BG, Farmer BT.; ''Molecular basis of MAPK-activated protein kinase 2:p38 assembly.''; PubMedEurope PMCScholia
Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMedEurope PMCScholia
Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA.; ''DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly.''; PubMedEurope PMCScholia
Kang SA, Lee ES, Yoon HY, Randazzo PA, Lee ST.; ''PTK6 inhibits down-regulation of EGF receptor through phosphorylation of ARAP1.''; PubMedEurope PMCScholia
Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H.; ''Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.''; PubMedEurope PMCScholia
Malumbres M, Pérez De Castro I, Hernández MI, Jiménez M, Corral T, Pellicer A.; ''Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b).''; PubMedEurope PMCScholia
Li YY, Wang L, Lu CD.; ''An E2F site in the 5'-promoter region contributes to serum-dependent up-regulation of the human proliferating cell nuclear antigen gene.''; PubMedEurope PMCScholia
Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S.; ''Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; 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
Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF.; ''Cyclin D activates the Rb tumor suppressor by mono-phosphorylation.''; PubMedEurope PMCScholia
Paternot S, Roger PP.; ''Combined inhibition of MEK and mammalian target of rapamycin abolishes phosphorylation of cyclin-dependent kinase 4 in glioblastoma cell lines and prevents their proliferation.''; PubMedEurope PMCScholia
Duronio RJ, O'Farrell PH.; ''Developmental control of a G1-S transcriptional program in Drosophila.''; PubMedEurope PMCScholia
Lukas SM, Kroe RR, Wildeson J, Peet GW, Frego L, Davidson W, Ingraham RH, Pargellis CA, Labadia ME, Werneburg BG.; ''Catalysis and function of the p38 alpha.MK2a signaling complex.''; PubMedEurope PMCScholia
Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ.; ''The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.''; PubMedEurope PMCScholia
Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS.; ''Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.''; PubMedEurope PMCScholia
Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, Feramisco JR, Wang JY, Knudsen ES.; ''RB-dependent S-phase response to DNA damage.''; PubMedEurope PMCScholia
Wells JM, Illenye S, Magae J, Wu CL, Heintz NH.; ''Accumulation of E2F-4.DP-1 DNA binding complexes correlates with induction of dhfr gene expression during the G1 to S phase transition.''; PubMedEurope PMCScholia
Wu CL, Kirley SD, Xiao H, Chuang Y, Chung DC, Zukerberg LR.; ''Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers.''; PubMedEurope PMCScholia
Wang Z, Xie Y, Zhang L, Zhang H, An X, Wang T, Meng A.; ''Migratory localization of cyclin D2-Cdk4 complex suggests a spatial regulation of the G1-S transition.''; PubMedEurope PMCScholia
Brown VD, Phillips RA, Gallie BL.; ''Cumulative effect of phosphorylation of pRB on regulation of E2F activity.''; PubMedEurope PMCScholia
Kukimoto I, Igaki H, Kanda T.; ''Human CDC45 protein binds to minichromosome maintenance 7 protein and the p70 subunit of DNA polymerase alpha.''; PubMedEurope PMCScholia
Haegebarth A, Heap D, Bie W, Derry JJ, Richard S, Tyner AL.; ''The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2.''; PubMedEurope PMCScholia
Chakraborty G, Jain S, Kundu GC.; ''Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms.''; PubMedEurope PMCScholia
McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR.; ''Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase.''; PubMedEurope PMCScholia
Bockstaele L, Kooken H, Libert F, Paternot S, Dumont JE, de Launoit Y, Roger PP, Coulonval K.; ''Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK "inhibitors".''; PubMedEurope PMCScholia
Bailly S, Fay M, Israël N, Gougerot-Pocidalo MA.; ''The transcription factor AP-1 binds to the human interleukin 1 alpha promoter.''; PubMedEurope PMCScholia
Fien K, Cho YS, Lee JK, Raychaudhuri S, Tappin I, Hurwitz J.; ''Primer utilization by DNA polymerase alpha-primase is influenced by its interaction with Mcm10p.''; PubMedEurope PMCScholia
Furukawa Y, Terui Y, Sakoe K, Ohta M, Saito M.; ''The role of cellular transcription factor E2F in the regulation of cdc2 mRNA expression and cell cycle control of human hematopoietic cells.''; PubMedEurope PMCScholia
Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA.; ''Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence.''; PubMedEurope PMCScholia
Zhang Y, Baranovskiy AG, Tahirov TH, Pavlov YI.; ''The C-terminal domain of the DNA polymerase catalytic subunit regulates the primase and polymerase activities of the human DNA polymerase α-primase complex.''; PubMedEurope PMCScholia
Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG.; ''Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes.''; PubMedEurope PMCScholia
Jäkel H, Weinl C, Hengst L.; ''Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control.''; PubMedEurope PMCScholia
Deacon K, Blank JL.; ''Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo.''; PubMedEurope PMCScholia
Lukong KE, Richard S.; ''Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration.''; PubMedEurope PMCScholia
Okazaki K, Sagata N.; ''The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells.''; PubMedEurope PMCScholia
Sharpless NE, Sherr CJ.; ''Forging a signature of in vivo senescence.''; PubMedEurope PMCScholia
New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J.; ''PRAK, a novel protein kinase regulated by the p38 MAP kinase.''; PubMedEurope PMCScholia
Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K, Roger PP.; ''Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase.''; PubMedEurope PMCScholia
James MK, Ray A, Leznova D, Blain SW.; ''Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity.''; PubMedEurope PMCScholia
Zhu W, Giangrande PH, Nevins JR.; ''E2Fs link the control of G1/S and G2/M transcription.''; 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
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
Lee S, Shuman JD, Guszczynski T, Sakchaisri K, Sebastian T, Copeland TD, Miller M, Cohen MS, Taunton J, Smart RC, Xiao Z, Yu LR, Veenstra TD, Johnson PF.; ''RSK-mediated phosphorylation in the C/EBP{beta} leucine zipper regulates DNA binding, dimerization, and growth arrest activity.''; PubMedEurope PMCScholia
Ainbinder E, Bergelson S, Pinkus R, Daniel V.; ''Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents.''; PubMedEurope PMCScholia
Li X, Lu Y, Liang K, Hsu JM, Albarracin C, Mills GB, Hung MC, Fan Z.; ''Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR.''; PubMedEurope PMCScholia
Xiang B, Chatti K, Qiu H, Lakshmi B, Krasnitz A, Hicks J, Yu M, Miller WT, Muthuswamy SK.; ''Brk is coamplified with ErbB2 to promote proliferation in breast cancer.''; PubMedEurope PMCScholia
Kamalati T, Jolin HE, Mitchell PJ, Barker KT, Jackson LE, Dean CJ, Page MJ, Gusterson BA, Crompton MR.; ''Brk, a breast tumor-derived non-receptor protein-tyrosine kinase, sensitizes mammary epithelial cells to epidermal growth factor.''; PubMedEurope PMCScholia
Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z.; ''Mdm2 association with p53 targets its ubiquitination.''; PubMedEurope PMCScholia
Quelle DE, Zindy F, Ashmun RA, Sherr CJ.; ''Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.''; PubMedEurope PMCScholia
Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR.; ''Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.''; PubMedEurope PMCScholia
Mizukami Y, Yoshioka K, Morimoto S, Yoshida Ki.; ''A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.''; PubMedEurope PMCScholia
Foulds CE, Nelson ML, Blaszczak AG, Graves BJ.; ''Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment.''; PubMedEurope PMCScholia
Saha P, Thome KC, Yamaguchi R, Hou Z, Weremowicz S, Dutta A.; ''The human homolog of Saccharomyces cerevisiae CDC45.''; PubMedEurope PMCScholia
Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ.; ''Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins.''; PubMedEurope PMCScholia
Peng M, Ball-Kell SM, Tyner AL.; ''Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse.''; PubMedEurope PMCScholia
Ohtani K, Tsujimoto A, Ikeda M, Nakamura M.; ''Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F.''; PubMedEurope PMCScholia
Nicke B, Bastien J, Khanna SJ, Warne PH, Cowling V, Cook SJ, Peters G, Delpuech O, Schulze A, Berns K, Mullenders J, Beijersbergen RL, Bernards R, Ganesan TS, Downward J, Hancock DC.; ''Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells.''; PubMedEurope PMCScholia
Hukkelhoven E, Liu Y, Yeh N, Ciznadija D, Blain SW, Koff A.; ''Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma.''; PubMedEurope PMCScholia
Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMedEurope PMCScholia
Liu N, Lucibello FC, Engeland K, Müller R.; ''A new model of cell cycle-regulated transcription: repression of the cyclin A promoter by CDF-1 and anti-repression by E2F.''; PubMedEurope PMCScholia
Jayadeva G, Kurimchak A, Garriga J, Sotillo E, Davis AJ, Haines DS, Mumby M, Graña X.; ''B55alpha PP2A holoenzymes modulate the phosphorylation status of the retinoblastoma-related protein p107 and its activation.''; PubMedEurope PMCScholia
Kato JY, Matsuoka M, Strom DK, Sherr CJ.; ''Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase.''; PubMedEurope PMCScholia
Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J.; ''A complex secretory program orchestrated by the inflammasome controls paracrine senescence.''; PubMedEurope PMCScholia
Regan Anderson TM, Peacock DL, Daniel AR, Hubbard GK, Lofgren KA, Girard BJ, Schörg A, Hoogewijs D, Wenger RH, Seagroves TN, Lange CA.; ''Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression.''; PubMedEurope PMCScholia
Ohtani K, DeGregori J, Nevins JR.; ''Regulation of the cyclin E gene by transcription factor E2F1.''; PubMedEurope PMCScholia
Sanidas I, Morris R, Fella KA, Rumde PH, Boukhali M, Tai EC, Ting DT, Lawrence MS, Haas W, Dyson NJ.; ''A Code of Mono-phosphorylation Modulates the Function of RB.''; PubMedEurope PMCScholia
Seidel JJ, Graves BJ.; ''An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.''; PubMedEurope PMCScholia
Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMedEurope PMCScholia
Avni D, Yang H, Martelli F, Hofmann F, ElShamy WM, Ganesan S, Scully R, Livingston DM.; ''Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage.''; PubMedEurope PMCScholia
Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M, Kishimoto T, Akira S.; ''Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6.''; PubMedEurope PMCScholia
Arata Y, Fujita M, Ohtani K, Kijima S, Kato JY.; ''Cdk2-dependent and -independent pathways in E2F-mediated S phase induction.''; PubMedEurope PMCScholia
Dhar SK, Delmolino L, Dutta A.; ''Architecture of the human origin recognition complex.''; PubMedEurope PMCScholia
Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H.; ''A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells.''; PubMedEurope PMCScholia
Masai H, Matsui E, You Z, Ishimi Y, Tamai K, Arai K.; ''Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks.''; PubMedEurope PMCScholia
Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H.; ''p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27.''; PubMedEurope PMCScholia
Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM.; ''Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.''; PubMedEurope PMCScholia
Fan G, Aleem S, Yang M, Miller WT, Tonks NK.; ''Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.''; PubMedEurope PMCScholia
Vashee S, Simancek P, Challberg MD, Kelly TJ.; ''Assembly of the human origin recognition complex.''; PubMedEurope PMCScholia
Nelson ML, Kang HS, Lee GM, Blaszczak AG, Lau DK, McIntosh LP, Graves BJ.; ''Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP.''; PubMedEurope PMCScholia
Desai D, Wessling HC, Fisher RP, Morgan DO.; ''Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2.''; PubMedEurope PMCScholia
Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, Yoshioka K, Ichijo H.; ''Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade.''; PubMedEurope PMCScholia
Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMedEurope PMCScholia
Li Y, Asahara H, Patel VS, Zhou S, Linn S.; ''Purification, cDNA cloning, and gene mapping of the small subunit of human DNA polymerase epsilon.''; PubMedEurope PMCScholia
Wang W, Nacusi L, Sheaff RJ, Liu X.; ''Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection.''; PubMedEurope PMCScholia
Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC.; ''Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.''; PubMedEurope PMCScholia
Liu S, Bolger JK, Kirkland LO, Premnath PN, McInnes C.; ''Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements.''; PubMedEurope PMCScholia
Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMedEurope PMCScholia
Hartupee J, Li X, Hamilton T.; ''Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.''; PubMedEurope PMCScholia
Atwood AA, Sealy LJ.; ''C/EBPβ's role in determining Ras-induced senescence or transformation.''; PubMedEurope PMCScholia
Patel P, Asbach B, Shteyn E, Gomez C, Coltoff A, Bhuyan S, Tyner AL, Wagner R, Blain SW.; ''Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4.''; PubMedEurope PMCScholia
Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J.; ''Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.''; PubMedEurope PMCScholia
Ishida N, Kitagawa M, Hatakeyama S, Nakayama K.; ''Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability.''; PubMedEurope PMCScholia
Kato JY, Matsuoka M, Polyak K, Massagué J, Sherr CJ.; ''Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation.''; PubMedEurope PMCScholia
Carrano AC, Eytan E, Hershko A, Pagano M.; ''SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.''; PubMedEurope PMCScholia
Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel EM, Waddell MB, Jäkel H, Kullmann M, Kriwacki RW, Hengst L.; ''Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases.''; PubMedEurope PMCScholia
Beijersbergen RL, Carlée L, Kerkhoven RM, Bernards R.; ''Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes.''; PubMedEurope PMCScholia
Izumi M, Yanagi K, Mizuno T, Yokoi M, Kawasaki Y, Moon KY, Hurwitz J, Yatagai F, Hanaoka F.; ''The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase.''; PubMedEurope PMCScholia
Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMedEurope PMCScholia
Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S.; ''3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region.''; PubMedEurope PMCScholia
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K.; ''The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.''; PubMedEurope PMCScholia
Bockstaele L, Bisteau X, Paternot S, Roger PP.; ''Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, evidence that CDK4 might not be activated by CDK7, and design of a CDK6 activating mutation.''; PubMedEurope PMCScholia
Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G.; ''Mitochondrial dysfunction contributes to oncogene-induced senescence.''; PubMedEurope PMCScholia
Le Gallic L, Virgilio L, Cohen P, Biteau B, Mavrothalassitis G.; ''ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression.''; PubMedEurope PMCScholia
Chattopadhyay S, Bielinsky AK.; ''Human Mcm10 regulates the catalytic subunit of DNA polymerase-alpha and prevents DNA damage during replication.''; PubMedEurope PMCScholia
Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D.; ''PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes.''; PubMedEurope PMCScholia
Ou L, Ferreira AM, Otieno S, Xiao L, Bashford D, Kriwacki RW.; ''Incomplete folding upon binding mediates Cdk4/cyclin D complex activation by tyrosine phosphorylation of inhibitor p27 protein.''; PubMedEurope PMCScholia
Tanizaki J, Okamoto I, Sakai K, Nakagawa K.; ''Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification.''; PubMedEurope PMCScholia
Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMedEurope PMCScholia
Kelly BL, Wolfe KG, Roberts JM.; ''Identification of a substrate-targeting domain in cyclin E necessary for phosphorylation of the retinoblastoma protein.''; PubMedEurope PMCScholia
Niehof M, Streetz K, Rakemann T, Bischoff SC, Manns MP, Horn F, Trautwein C.; ''Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.''; PubMedEurope PMCScholia
Lukong KE, Larocque D, Tyner AL, Richard S.; ''Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression.''; PubMedEurope PMCScholia
Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMedEurope PMCScholia
Atwood AA, Sealy L.; ''Regulation of C/EBPbeta1 by Ras in mammary epithelial cells and the role of C/EBPbeta1 in oncogene-induced senescence.''; PubMedEurope PMCScholia
Jiang W, Wells NJ, Hunter T.; ''Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.''; PubMedEurope PMCScholia
Leng X, Noble M, Adams PD, Qin J, Harper JW.; ''Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4.''; PubMedEurope PMCScholia
Zheng Y, Asara JM, Tyner AL.; ''Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 CRK-associated substrate.''; PubMedEurope PMCScholia
Orend G, Hunter T, Ruoslahti E.; ''Cytoplasmic displacement of cyclin E-cdk2 inhibitors p21Cip1 and p27Kip1 in anchorage-independent cells.''; PubMedEurope PMCScholia
Bagui TK, Jackson RJ, Agrawal D, Pledger WJ.; ''Analysis of cyclin D3-cdk4 complexes in fibroblasts expressing and lacking p27(kip1) and p21(cip1).''; PubMedEurope PMCScholia
Tedesco D, Lukas J, Reed SI.; ''The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2).''; PubMedEurope PMCScholia
Yu B, Lane ME, Pestell RG, Albanese C, Wadler S.; ''Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein.''; PubMedEurope PMCScholia
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K.; ''The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.''; PubMedEurope PMCScholia
Ono H, Basson MD, Ito H.; ''PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling.''; PubMedEurope PMCScholia
Reynisdóttir I, Massagué J.; ''The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.''; PubMedEurope PMCScholia
Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH.; ''Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.''; PubMedEurope PMCScholia
Castro NE, Lange CA.; ''Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.''; PubMedEurope PMCScholia
Lundberg AS, Weinberg RA.; ''Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.''; 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
Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K.; ''EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.''; PubMedEurope PMCScholia
Galaktionov K, Chen X, Beach D.; ''Cdc25 cell-cycle phosphatase as a target of c-myc.''; PubMedEurope PMCScholia
DeGregori J, Kowalik T, Nevins JR.; ''Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes.''; PubMedEurope PMCScholia
Ohtani K, DeGregori J, Leone G, Herendeen DR, Kelly TJ, Nevins JR.; ''Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor.''; PubMedEurope PMCScholia
Vigo E, Müller H, Prosperini E, Hateboer G, Cartwright P, Moroni MC, Helin K.; ''CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase.''; PubMedEurope PMCScholia
Chu I, Sun J, Arnaout A, Kahn H, Hanna W, Narod S, Sun P, Tan CK, Hengst L, Slingerland J.; ''p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.''; PubMedEurope PMCScholia
Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMedEurope PMCScholia
Goel RK, Lukong KE.; ''Tracing the footprints of the breast cancer oncogene BRK - Past till present.''; PubMedEurope PMCScholia
Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E.; ''Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.''; PubMedEurope PMCScholia
Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF.; ''Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing.''; PubMedEurope PMCScholia
Ikeda O, Mizushima A, Sekine Y, Yamamoto C, Muromoto R, Nanbo A, Oritani K, Yoshimura A, Matsuda T.; ''Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.''; PubMedEurope PMCScholia
Ikeda O, Sekine Y, Mizushima A, Nakasuji M, Miyasaka Y, Yamamoto C, Muromoto R, Nanbo A, Oritani K, Yoshimura A, Matsuda T.; ''Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells.''; PubMedEurope PMCScholia
Zheng Y, Peng M, Wang Z, Asara JM, Tyner AL.; ''Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor.''; PubMedEurope PMCScholia
Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH.; ''Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin.''; PubMedEurope PMCScholia
Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A.; ''The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27.''; PubMedEurope PMCScholia
Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMedEurope PMCScholia
Walter J, Newport J.; ''Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.''; PubMedEurope PMCScholia
Li Y, Pursell ZF, Linn S.; ''Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.''; PubMedEurope PMCScholia
Clifton AD, Young PR, Cohen P.; ''A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress.''; PubMedEurope PMCScholia
Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P.; ''Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2.''; PubMedEurope PMCScholia
Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M.; ''Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.''; PubMedEurope PMCScholia
Vijayachandra K, Lee J, Glick AB.; ''Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model.''; PubMedEurope PMCScholia
Gao Y, Cimica V, Reich NC.; ''Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3.''; PubMedEurope PMCScholia
Takekawa M, Tatebayashi K, Saito H.; ''Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.''; PubMedEurope PMCScholia
Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G.; ''DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.''; PubMedEurope PMCScholia
Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y.; ''pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.''; PubMedEurope PMCScholia
Lal A, Kim HH, Abdelmohsen K, Kuwano Y, Pullmann R, Srikantan S, Subrahmanyam R, Martindale JL, Yang X, Ahmed F, Navarro F, Dykxhoorn D, Lieberman J, Gorospe M.; ''p16(INK4a) translation suppressed by miR-24.''; PubMedEurope PMCScholia
Kardinal C, Dangers M, Kardinal A, Koch A, Brandt DT, Tamura T, Welte K.; ''Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4.''; PubMedEurope PMCScholia
Fan G, Lin G, Lucito R, Tonks NK.; ''Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells.''; PubMedEurope PMCScholia
Aprelikova O, Xiong Y, Liu ET.; ''Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase.''; PubMedEurope PMCScholia
Sgouras DN, Athanasiou MA, Beal GJ, Fisher RJ, Blair DG, Mavrothalassitis GJ.; ''ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation.''; PubMedEurope PMCScholia
Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.
Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).
MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).
Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).
Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.
Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).
MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).
p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).
Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.
IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).
Please refer to Young and Narita 2009 for a recent review.
PTK6 (BRK) is an oncogenic non-receptor tyrosine kinase that functions downstream of ERBB2 (HER2) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). Since ERBB2 forms heterodimers with EGFR and since MET can heterodimerize with both ERBB2 and EGFR (Tanizaki et al. 2011), it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2. Levels of PTK6 increase under hypoxic conditions (Regan Anderson et al. 2013, Pires et al. 2014). The kinase activity of PTK6 is negatively regulated by PTPN1 phosphatase (Fan et al. 2013) and SRMS kinase (Fan et al. 2015), as well as the STAT3 target SOCS3 (Gao et al. 2012).
PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).
PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).
PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).
PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.
For a review of PTK6 function, please refer to Goel and Lukong 2015.
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).
The pRB C-terminus contains a cluster of seven candidate in vivo cdk phosphorylation sites (residues 795, 807, 811, 821, and 826) and is phosphorylated in vitro by cyclin A, cyclin E, and cyclin D-associated kinases.
At the beginning of this reaction, 1 molecule of 'phospho-Retinoblastoma protein', and 1 molecule of 'RNA primer-DNA primer:origin duplex with DNA damage' are present. At the end of this reaction, 1 molecule of 'Rb1:RNA primer-DNA primer:origin duplex with DNA damage' is present.
This reaction takes place in the 'nucleus' and is mediated by the 'phosphoprotein phosphatase activity' of 'PP2A'.
At the beginning of this reaction, 1 molecule of 'RNA primer-DNA primer:origin duplex' is present. At the end of this reaction, 1 molecule of 'DNA polymerase alpha:primase', and 1 molecule of 'RNA primer-DNA primer:origin duplex with DNA damage' are present. This reaction takes place in the 'nucleus' (Gambus et al. 2009, Remus et al. 2009, Chattopadhyay et al.2007, Fien et al. 2004).
This event is inferred from the fission yeast. Cyclin B activity is thought to inhibit pre-RC formation by first associating with ORC during DNA replication.
This set of events is inferred from annotated events in Drosophila.
Rb1 is normally hyperphosphorylated by CycD/CDK4/CDK6 and Cyclin E/CDK2 for transition into S-phase. PP2A can then reverse this reaction, in this case, in response to DNA damage induced checkpoint.
At G1 entry from G0, p130 (RBL2) is phosphorylated on three threonine and serine residues by cyclin D1 dependent kinases CDK4 and/or CDK6, leading to dissociation of p130 (RBL2) from complexes it formed with E2F4 or E2F5 and DP1 or DP2. This is thought to promote translocation of E2F4 and E2F5, which lack nuclear localization signals, to the cytosol, allowing activating E2Fs (E2F1, E2F2 and E2F3) to bind E2F promoters and activate transcription of genes needed for G1 progression.
In late G1, cyclin D dependent kinases CDK4 and CDK6 phosphorylate RBL1 (p107) on four serine and threonine residues (S964, S975, T369 and S640), leading to dissociation of phosphorylated RBL1 (p107) from E2F4 in complex with either DP-1 or DP-2. E2F4, which lacks nuclear localization signal, is then thought to translocate to the cytosol, allowing E2F promoter sites to become occupied by activating E2Fs (E2F1, E2F2, and E2F3), resulting in transcription of E2F targets needed for cell cycle progression.
p130 (RBL2) in complex with E2F4 or E2F5 and DP1 or DP2 recruits histone deacetylase HDAC1, probably in complex with other chromatin modification factors, and represses transcription of E2F target promoters during G0 in quiescent cells.
p107 (RBL1) in complex with E2F4 and DP1 or DP2 recruits histone deacetylase HDAC1 (possibly in complex with other chromatin modification proteins) through LXCXE-like motif, shared by pocket proteins, to repress transcription of E2F target genes in early G1.
In G0 and early G1, p130 (RBL2) bound to E2F4 or E2F5 and DP1 or DP2 associates with the MuvB complex, consisting of LIN9, LIN37, LIN52, LIN54 and RBBP4 to form evolutionarily conserved DREAM complex. Phosphorylation of LIN52 on serine residue S28 is critical for association of MuvB complex with p130 (RBL2).
LIN52 subunit of MuvB complex is phosphorylated by the protein kinase DYRK1A on the serine residue S28, promoting association of MuvB with p130 (RBL2). From model organism studies, DYRK proteins are known to function in cell cycle regulation, differentiation and stress response.
Dephosphorylation of p107 (RBL1) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p107 (RBL1), through counteracting action of cyclin dependent kinases (CDKs) throughout the cell cycle. It is assumed that PP2A dephosphorylates p107 (RBL1) on all four phosphorylation sites, but further experiments are needed to confirm this.
Dephosphorylation of p130 (RBL2) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p130 (RBL2), through counteracting action of cyclin dependent kinases (CDKs). It is assumed that PP2A dephosphorylates p130 (RBL2) on all three phosphorylation sites, but further experiments are needed to confirm this.
p130 (RBL2) in complex with E2F4/5 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth.
p130 (RBL2) is able to bind complexes of CDK2 with either cyclin A or cyclin E through the cyclin-binding LFG motif within the pocket domain, which is conserved in p107 (RBL1) and p21/WAF1/Cip1 family of cyclin-dependent kinases. In addition to LFG motif, amino terminal region of p130 (RBL2), conserved in p107 (RBL1), is necessary for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction.
p107 (RBL1) in complex with E2F4 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth.
p107 (RBL1) is able to bind complexes of CDK2 with either cyclin A or cyclin E, through cyclin-binding LFG motif in the pocket domain, which is conserved in p130 (RBL2) and p21/WAF1/Cip1 family of cyclin-dependent kinase inhibitors. In addition to the LFG motif, the amino terminal sequence conserved in the p107 (RBL1) and p130 (RBL2) is needed for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction.
Phosphorylated p130 (RBL2) binds SCF (Skp2) ubiquitin ligase in complex with Cks1. Phosphorylation of p130 (RBL2) serine residue S672 by CDK4/6 is critical for this interaction.
As quiescent G0 cells reenter the cell cycle, p130 (RBL2) is phosphorylated by CDK4/6. This phosphorylated p130 (RBL2) binds ubiquitin ligase SCF (Skp2) in complex with Cks1, and is subsequently ubiquitinated and degraded similarly to p27, which is another target of SCF (Skp2).
Prior to mitogen activation, the inhibitory proteins of the INK4 family (p15, p16, p18, and p19) associate with the catalytic domains of free CDK4 and CDK6, preventing their association with D type cyclins (CCND1, CCND2 and CCND3), and thus their activation (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995). Inactivation and defects of RB1 strongly upregulate p16-INK4A (Parry et al. 1995).
p27 translocates to the nucleoplasm where it associates with CyclinE:Cdk2 complexes. Localization of p27 to the nucleus is necessary to inhibit Cdk activation by Cdk-activating kinase.
The interaction between the Skp2 subunit of the SCF(Skp2) complex and p27 is dependent upon Cdk2:Cyclin A/E mediated phosphorylation of p27 at Thr 187 (Carrano et al, 1999; Tsvetkov et al, 1999). There is evidence that Cyclin A/B:Cdk1 can also bind and phosphorylate p27 on Thr 187 (Nakayama et al., 2004). This phosphorylation is also essential for the subsequent ubiquitination of p27.
The accessory protein, Cks1 promotes efficient interaction between phosphorylated p27 and the SCF (Skp2) complex (Ganoth et al., 2001; Spruck et al., 2001). Cks1 binds to Skp2 in the leucine-rich repeat (LRR) domain and C-terminal tail (Hao et al., 2005). The phosphorylated Thr187 side chain of p27 associates with a phosphate binding site on Cks1, and the side chain containing Glu185 is positioned in the interface between Skp2 and Cks1 where it interacts with both (Hao et al., 2005).
Binding of the MYC:MAX heterodimer to MYC response elements in the first and second intron of the CDC25A gene activates CDC25A transcription in mid to late G1 (Galaktionov et al. 1996). Transcription of the CDC25A gene can be directly activated by E2F1 (DeGregori et al. 1995, Vigo et al. 1999). Transcription of the CDC25A gene is directly inhibited by the DREAM complex (Litovchick et al. 2007).
Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK kinase activity. The association of p21/p27 with the Cyclin A/E:Cdk2 complex prevents CAK mediated phosphorylation of Cdk2 (Aprelikova et al., 1995).
pRB contains, in its C terminus, a cyclin-cdk interaction motif like that found in E2F1 and p21 that enables it to be recognized and phosphorylated by cyclin-cdk complexes.
Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
DNA polymerase alpha:primase is comprised of four subunits, p180, p70, p58, and p49. The two primase subunits, p58 and p49, form a tight complex. The p49 subunit contains the DNA primase activity and one role of p58 appears to be tethering p49 to p180, the DNA polymerase catalytic subunit. The fourth subunit, p70, binds p180 and may tether the DNA polymerase alpha:primase complex to Cdc45.
After pre-RC assembly and Cdc45 association with the origin of replication, Replication Protein A (RPA) also associates with chromatin. RPA is a heterotrimeric complex containing p70, p34, and p11 subunits, and also is required for DNA recombination and DNA repair. The p70 subunit of RPA binds to the primase subunits of Pol alpha:primase. The p70 and p34 subunits of RPA are phosphorylated in a cell cycle-dependent manner. RPA is a single-strand DNA (ssDNA) binding protein and its association with chromatin at this stage suggests that DNA is partially unwound. This suggestion has been confirmed by detection of ssDNA in budding yeast origins of replication using chemical methods.
Once the Mcm2-7 complex has been assembled onto the origin of replication, the next step is the assembly of Cdc45, an essential replication protein, in late G1. The assembly of Cdc45 onto origins of replication forms a complex distinct from the pre-replicative complex, sometimes called the pre-initiation complex. The assembly of Cdc45 onto origins correlates with the time of initiation. Like the Mcm2-7 proteins, Cdc45 binds specifically to origins in the G1 phase of the cell cycle and then to non-origin DNA during S phase and is therefore thought to travel with the replication fork. Indeed, S. cerevisiae Cdc45 is required for DNA replication elongation as well as replication initiation. Cdc45 is required for the association of alpha DNA polymerase:primase with chromatin. Based on this observation and the observation that in S. cerevisiae, cCdc45 has been found in large complexes with some components of Mcm2-7 complex, it has been suggested that Cdc45 plays a scaffolding role at the replication fork, coupling Pol-alpha:primase to the replication fork through the helicase. Association of Cdc45 with origin DNA is regulated in the cell cycle and its association is dependent on the activity of cyclin-dependent kinases but not the Cdc7/Dbf4 kinase. In Xenopus egg extracts, association of Cdc45 with chromatin is dependent on Xmus101. TopBP1, the human homolog of Xmus1, is essential for DNA replication and interacts with DNA polymerase epsilon, one of the polymerases involved in replicating the genome. TopBP1 homologs have been found in S. cerevisiae and S. pombe. Sld3, an additional protein required for Cdc45 association with chromatin in S. cerevisiae and S. pombe, has no known human homolog.
At the beginning of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', 1 molecule of 'DDK', and 1 molecule of 'CDK' are present. At the end of this reaction, 1 molecule of 'CDK:DDK:Mcm10:pre-replicative complex' is present.
MCM10 is required for human DNA replication. In S. cerevisiae, Mcm10, like Mcm2-7, is required for minichromosome maintenance, but Mcm10 has no sequence homology with these other proteins (Merchant et al., 1997). Genetic studies have demonstrated that Mcm10 is required for DNA replication in S. pombe (Aves et al., 1998) and S. cerevisiae cells (Homesley et al., 2000) and immunodepletion of XlMcm10 interferes with DNA replication in Xenopus egg extracts (Wohlschlegel et al., 2002). Human Mcm10 interacts with chromatin in G1 phase and then dissociates during G2 phase. In S. cerevisiae, Mcm10 has been shown to localize to origins during G1 (Ricke and Bielinsky, 2004), and it may stabilize the association of Mcm2-7 with the pre-replicative complex (Sawyer et al., 2004). This timing of association is consistent with studies that demonstrate that, in Xenopus egg extracts, Mcm10 is required for association of Cdc45, but not Mcm2-7 with chromatin. Biochemical evidence that Mcm10 plays a direct role in the activation of the pre-replicative complex includes the requirement for SpMcm10 in the phosphorylation of the Mcm2-7 complex by DDK (Lee et al., 2004) and the fact that SpMcm10 binds and stimulates DNA polymerase alpha activity (Fien et al., 2004).
At the beginning of this reaction, 1 molecule of 'Mcm10:pre-replicative complex' is present. At the end of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', and 1 molecule of 'CDT1' are present.
At the beginning of this reaction, 1 molecule of 'Mcm2-7 complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phosphorylated Mcm2-7 complex', and 1 molecule of 'ADP' are present.
This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.
At the beginning of this reaction, 1 molecule of 'origin of replication', and 1 molecule of 'DNA polymerase epsilon' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon:origin complex' is present.
The E-type cyclins and Cyclin Dependent Kinase 2 control the transition from G1 to S phase. Cdk2 is competent to carry out the necessary reactions only when complexed with Cyclin E.
During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
Activated PTK6 (BRK) binds to CDKN1B (p27KIP1) that is in a complex with CDK4 and cyclin D1 (CCND1). Since PTK6 increases cyclin E1 (CCNE1) levels downstream of ERBB2 while decreasing CDKN1B levels, PTK6 probably also associates with CDKN1B bound to the complex of CCNE1 and CDK2 (Xiang et al. 2008).
PTK6 (BRK) phosphorylates CDKN1B (p27KIP1) bound to the complex of CDK4 and CCND1 (cyclin D1) on tyrosine residue Y88 and possibly other tyrosines (e.g. Y89) (Patel et al. 2015). Based on the finding that PTK6 promotes ERBB2-induced increase in cyclin E1 (CCNE1) levels and decrease in CDKN1B levels (Xiang et al. 2008), and supported by the analogy with other SRC family kinases that phosphorylate CDKN1B (Grimmler et al. 2007), PTK6 is likely to also phosphorylate CDKN1B bound to the complex of CCNE1 and CDK2. Phosphorylation of CDKN1B (p27KIP1) on tyrosine residue Y88 by SRC family kinases dislodges the 3-10 helix of CDKN1B from the active site of CDK2 or CDK4, thus converting CDKN1B from a bound inhibitor to a bound non-inhibitor (Grimmler et al. 2007, Ray et al. 2009).
The cyclin dependent kinase CDK4 or CDK6 forms a complex with one of the cyclin D family (CCND) members: cyclin D1 (CCND1), cyclin D2 (CCND2) or cyclin D3 (CCND3) (Matsushime et al. 1992, Meyerson and Harlow 1994, La Baer et al. 1997, Bagui et al. 2003, Cerqueira et al. 2014). This association is regulated by mitogenic pathways (Cheng et al. 1998, Depoortere et al. 1998). While the binding of Cip/Kip CDK-inhibitors (CDKIs) (CDKNA1 - p21Cip, CDKN1B - p27Kip or CDKN1C - p57Kip2) stabilizes CDK4/6:CCND complexes by decreasing their dissociation rate (La Baer et al. 1997; reviewed by Sherr and Roberts 1999), CIP/KIP CDKIs are not needed for binding of CDK4 or CDK6 to CCNDs and activity of CDK4/6:CCND complexes (Bagui et al. 2000, Sugimoto et al. 2002, Bagui et al. 2003, Cerqueira et al. 2014; reviewed by Bockstaele et al 2006).
Binding of CDK inhibitors of the Cip/Kip family, CDKNA1 (p21Cip), CDKN1B (p27Kip) or CDKN1C (p57Kip2) to the complex of CDK4 or CDK6 and cyclin D family members (CCND1, CCND2 or CCND3), inhibits kinase activity of the CDK4/6:CCND complexes but at the same time increases their stability and, hence, their abundance (La Baer et al. 1997, Bagui et al. 2003, Cerqueira et al. 2014; reviewed by Bockstaele et al. 2006). Based on structural studies of CDKN1B, Cip/Kip inhibitors simultaneously interact with CDK4/6 and CCNDs (Liu et al. 2010). Phosphorylation of CDKN1B on threonine residues T157 and T198 by activated AKT in early G1 may precede binding of CDKN1B to CDK4/6:CCND complexes (Larrea et al. 2008).
Phosphorylation of Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip), CDKN1B (p27Kip1) and CDKN1C (p57Kip2) on conserved tyrosine residues Y77, Y88 and Y91, respectively, can convert them from bound inhbitors to bound non-inhibitors of CDK4 or CDK6 complexes with D cyclins by dislodging them from the active site of CDK4 or CDK6. This mechanism was studied in most detail on the example of CDKN1B associated with the CDK2:CCNA complex (Grimmler et al. 2007) and the CDK4:CCND1 complex (James et al. 2008, Patel et al. 2015). For a review of this topic, please refer to Blain 2008. CDKN1A can be phosphorylated at tyrosine residue Y77 by protein tyrosine kinase ABL1 (Hukkelhoven et al. 2012). CDKN1B can be phosphorylated at tyrosine residue Y88, and probably also at the adjacent Y89, by protein tyrosine kinases ABL1 (Grimmler et al. 2007, James et al. 2008, Ray et al. 2009, Ou et al. 2011), LYN (Grimmler et al. 2007), SRC (Larrea et al. 2008), JAK2 (Jakel et al. 2011) and PTK6 (Patel et al. 2015). CDKN1C can be phosphorylated at tyrosine residue Y91 by protein tyrosine kinase ABL1 (Borriello et al. 2011). Dislodgment of the tyrosine phosphorylated 3-10 helix of Cip/Kip CDK inhibitors from the active site of cyclin D-bound CDK4 or CDK6 results in increased catalytic activity of CDK4 or CDK6 by allowing ATP binding to the active site, but also by enabling activating phosphorylation of the T-loop of CDK4 or CDK6 phosphorylation by CDK7 in complex with cyclin H (Ray et al. 2009). SRC-mediated phosphorylation of CDKN1B on tyrosine residue Y88 was shown to reduce protein stability of CDKN1B (Chu et al. 2007). Without overexpression of BCR-ABL or SRC-family tyrosine kinases in several cell systems, tyrosine phosphorylated p27 is either undetectable or a very low abundance species (Ishida et al. 2000, Jaimes et al. 2008, Grimmler et al. 2007) that does not bind preferentially to CDK4 (Jaimes et al. 2008). Therefore, tyrosine phosphorylation of p27 is unlikely to be the sole explanation of the full activity of p27-bound CDK4:CCND complexes reported in previous studies (Blain et al. 1997, Coulonval et al. 2003, Bockstaele et al. 2006). It has been proposed that stoichiometry of the Cip/Kip complex with CDK4 or CDK6 and cyclin D, in addition to or alternative to tyrosine phosphorylation of Cip/Kip CDK inhibitors, determines their inhibitory role where binding of more than one molecule of CDKN1A, CDKN1B or CDKN1C would be needed to achieve inhibition of the CDK4/6:CCND complex (reviewed by Paternot et al. 2010).
T-loop phosphorylation of CDK4 and CDK6 on threonine residues T172 and T177, respectively, is necessary for catalytic activity of complexes of CDK4 and CDK6 with D-type cyclins (CCND1, CCND2 and CCND3) (Kato, Matsuoka, Strom and Sherr 1994, Merzel-Schachter et al. 2013, Bisteau et al. 2013). These phosphorylations depend on prior D type cyclin binding (Kato, Matsuoka, Polyak et al. 1994, Bockstaele et al. 2006). The T-loop phosphorylation is not precluded by the association of CDK4/6:CCND complexes to Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip) and CDKN1B (p27Kip1), however high expression levels of CDKN1B reduce the T172 phosphorylation of CDK4 (Kato, Matsuoka, Polyak et al. 1994, Bockstaele et al. 2006, Ray et al. 2009). Phosphorylation at tyrosine residue Y89 of CDKN1B (p27Kip1) bound to CDK4:CCND complexes was found to be necessary for phosphorylation of CDK4 by the CAK complex (composed of CDK7, CCNH and MAT1) in vitro, but not for the phosphorylation by CSK1 of S. pombe (Ray et al. 2009). T-loop phosphorylations of CDK4 and CDK6 are differentially regulated (Bockstaele et al. 2009). Especially, the T172 phosphorylation of CDK4 is strictly controlled by mitogenic and antimitogenic pathways (Paternot and Roger 2009), and it can be differentially regulated in cyclin D1:CDK4 and cyclin D3:CDK4 complexes (reviewed by Paternot et al. 2010). The T-loop T172 phosphorylation motif of CDK4 differs from the other cell cycle CDKs, including CDK6, by the presence of an adjacent proline residue (P173) that is evolutionarily conserved. This proline residue is required for T172 phosphorylation of CDK4 in vivo, but not for its in vitro phosphorylation by CAK. This indicates that CDK4 might be activated by other proline-directed kinases in vivo (Bockstaele et al. 2009). Nevertheless, in HCT116 colon carcinoma cell line, the activity of CDK7 is required for the T172 phosphorylation of CDK4 and the activity of CDK4/6:CCND complexes (Merzel Schachter et al. 2013, Bisteau et al. 2013). T170 phosphorylation of CDK7 facilitates the activity of CAK on CDK4 (Merzel Schachter et al. 2013). However, CDK7 inhibition in HCT116 cells does not preclude the T172 phosphorylation of CDK4:CCND complexes that are not associated with CDKN1A (Bisteau et al. 2013). Phosphorylation of CDKN1A at serine residue S130 by CDK4/6 and CDK2 has been implicated as a pre-requisite for CAK-mediated phosphorylation of CDKN1A-bound CDK4 (Bisteau et al. 2013). Other kinases involved in phosphorylation of CDK4 at T172 remain to be defined (Bockstaele et al. 2009, Bisteau et al. 2013, reviewed by Paternot et al. 2010).
E2F1 directly stimulates transcription of the CDC6 gene (Yan et al., 1998; Ohtani et al., 1998). CDC6 is required to recruit the MCM2-7 replication helicases. Transcription of the CDC6 gene is directly repressed by the DREAM complex (Litovchick et al. 2007).
E2F1 binds to E2F binding sites in the promoter of the CDC6 gene (Yan et al., 1998; Ohtani et al., 1998). CDC6 is required to recruit the MCM2-7 replication helicases.
E2F1 binds to E2F binding sites in the promoter of the POLA1 gene, stimulating POLA1 transcription. POLA1 encodes the catalytic subunit p180 of the DNA polymerase alpha (DeGregori et al. 1995, Giangrande et al. 2004). Activation of POLA1 by E2F1 has also been demonstrated in Drosophila (Ohtani and Nevins 1994).
E2F1 binds to E2F binding sites in the promoter of the POLA1 gene, encoding the DNA polymerase alpha catalytic subunit p180 (DeGregori et al. 1995, Giangrande et al. 2004).
E2F1 binds to E2F binding sites in the promoter of the PCNA gene, encoding the proliferating cell nuclear antigen, a component of the DNA polymerase complex involved in eukaryotic DNA replication (DeGregori et al. 1995, Li et al. 2003).
E2F1 directly stimulates transcription of the PCNA gene, which encodes the proliferating cell nuclear antigen, a component of the DNA polymerase complex involved in eukaryotic DNA replication (DeGregori et al. 1995, Li et al. 2003). The PCNA gene transcription is directly repressed by the DREAM complex (Litovchick et al. 2007).
E2F1 binds to E2F binding sites in the promoter of the ORC1 gene (Ohtani et al. 1996, Ohtani et al. 1998). It has been observed in Drosophila that E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication (Asano and Wharton, 1999).
E2F1 directly stimulates transcription of the ORC1 gene (Ohtani et al. 1996, Ohtani et al. 1998). E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication in Drosophila (Asano and Wharton, 1999).
E2F1 directly stimulates transcription of the CCNE1 gene, encoding cyclin E1 (DeGregori et al. 1995, Ohtani et al. 1995).Cyclin E proteins play an important role in the transition from G1 to S-phase by associating with CDK2.
E2F1 binds to E2F binding sites in the promoter of the DHFR gene, encoding dihydrofolate reductase. DHFR is involved in folate metabolism and synthesis of DNA bases (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999).
E2F1 directly stimulates transcription of the DHFR gene, encoding dihydrofolate reductase. DHFR is involved in folate metabolism and synthesis of DNA bases (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999).
E2F1 directly stimulates transcription of the CDC45 gene (Arata et al. 2000), encoding Cell division control protein 45 homolog, which is required for initiation of DNA replication.
E2F1 binds to E2F binding sites in the promoter of the CDK1 gene, encoding cyclin-dependent kinase 1 (Cdc2) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004).
E2F1 directly stimulates transcription of the CDK1 gene, encoding cyclin-dependent kinase 1 (Cdc2) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004). Transcription of the CDK1 gene is directly inhibited by complexes of HDAC1 and RBL1 (p107) or RBL2 (p130) in G1 and G0, respectively (Rayman et al. 2002).
E2F1 binds to E2F binding sites in the promoter of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004).
E2F1 directly stimulates transcription of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004). Binding of E2F6 to the RRM2 gene promoter inhibits RRM2 transcription (Bertoli et al. 2013).
E2F1 binds to E2F binding sites in the promoter of the TK1 gene, encoding thymidine kinase (Dou et al. 1994, DeGregori et al. 1995, Giangrande et al. 2004).
Expression of the TYMS gene, encoding thymidylate synthase, is positively regulated by E2F1, but direct regulation has not been demonstrated (DeGregori et al. 1995).
Transcription of the E2F1 gene is directly inhibited by the DREAM complex (Litovchick et al. 2007). E2F1 transcription is also directly inhibited by the complex of HDAC1 and RBL1 (p107) or RBL2 (p130) (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the E2F1 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the MYBL2 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CDK1 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CCNA2 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CCNA2 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 directly inhibit transcription from the MYBL2 gene (Rayman et al. 2002).
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pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45pre-replicative
complexB:CDK1:ORC:origin
of replicationalpha:primase:DNA polymerase alpha:origin
complexepsilon:origin
complexpre-replicative
complexOncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).
MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).
Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).
Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.
MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).
p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).
primer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin
duplexHere, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.
IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).
Please refer to Young and Narita 2009 for a recent review.
PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).
PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).
PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).
PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.
For a review of PTK6 function, please refer to Goel and Lukong 2015.
activity of SMAD2/SMAD3:SMAD4
heterotrimerAnnotated Interactions
pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45pre-replicative
complex:CDC45pre-replicative
complexpre-replicative
complexB:CDK1:ORC:origin
of replicationalpha:primase:DNA polymerase alpha:origin
complexepsilon:origin
complexepsilon:origin
complexpre-replicative
complexpre-replicative
complexThis reaction takes place in the 'nucleus' and is mediated by the 'phosphoprotein phosphatase activity' of 'PP2A'.
This reaction takes place in the 'nucleus' (Gambus et al. 2009, Remus et al. 2009, Chattopadhyay et al.2007, Fien et al. 2004).
Rb1 is normally hyperphosphorylated by CycD/CDK4/CDK6 and Cyclin E/CDK2 for transition into S-phase. PP2A can then reverse this reaction, in this case, in response to DNA damage induced checkpoint.
Transcription of the CDC25A gene can be directly activated by E2F1 (DeGregori et al. 1995, Vigo et al. 1999).
Transcription of the CDC25A gene is directly inhibited by the DREAM complex (Litovchick et al. 2007).
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.
CDKN1A can be phosphorylated at tyrosine residue Y77 by protein tyrosine kinase ABL1 (Hukkelhoven et al. 2012). CDKN1B can be phosphorylated at tyrosine residue Y88, and probably also at the adjacent Y89, by protein tyrosine kinases ABL1 (Grimmler et al. 2007, James et al. 2008, Ray et al. 2009, Ou et al. 2011), LYN (Grimmler et al. 2007), SRC (Larrea et al. 2008), JAK2 (Jakel et al. 2011) and PTK6 (Patel et al. 2015). CDKN1C can be phosphorylated at tyrosine residue Y91 by protein tyrosine kinase ABL1 (Borriello et al. 2011).
Dislodgment of the tyrosine phosphorylated 3-10 helix of Cip/Kip CDK inhibitors from the active site of cyclin D-bound CDK4 or CDK6 results in increased catalytic activity of CDK4 or CDK6 by allowing ATP binding to the active site, but also by enabling activating phosphorylation of the T-loop of CDK4 or CDK6 phosphorylation by CDK7 in complex with cyclin H (Ray et al. 2009).
SRC-mediated phosphorylation of CDKN1B on tyrosine residue Y88 was shown to reduce protein stability of CDKN1B (Chu et al. 2007).
Without overexpression of BCR-ABL or SRC-family tyrosine kinases in several cell systems, tyrosine phosphorylated p27 is either undetectable or a very low abundance species (Ishida et al. 2000, Jaimes et al. 2008, Grimmler et al. 2007) that does not bind preferentially to CDK4 (Jaimes et al. 2008). Therefore, tyrosine phosphorylation of p27 is unlikely to be the sole explanation of the full activity of p27-bound CDK4:CCND complexes reported in previous studies (Blain et al. 1997, Coulonval et al. 2003, Bockstaele et al. 2006). It has been proposed that stoichiometry of the Cip/Kip complex with CDK4 or CDK6 and cyclin D, in addition to or alternative to tyrosine phosphorylation of Cip/Kip CDK inhibitors, determines their inhibitory role where binding of more than one molecule of CDKN1A, CDKN1B or CDKN1C would be needed to achieve inhibition of the CDK4/6:CCND complex (reviewed by Paternot et al. 2010).
In the absence of Cip/Kip proteins, a small number of CDK4/6:CCND complexes enter the nucleus through an unknown mechanism and phosphorylate target proteins (Bagui et al. 2003).
Phosphorylation of CDKN1A at serine residue S130 by CDK4/6 and CDK2 has been implicated as a pre-requisite for CAK-mediated phosphorylation of CDKN1A-bound CDK4 (Bisteau et al. 2013). Other kinases involved in phosphorylation of CDK4 at T172 remain to be defined (Bockstaele et al. 2009, Bisteau et al. 2013, reviewed by Paternot et al. 2010).
Transcription of the CDC6 gene is directly repressed by the DREAM complex (Litovchick et al. 2007).
The PCNA gene transcription is directly repressed by the DREAM complex (Litovchick et al. 2007).
primer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin
duplex