Transcriptional regulation by RUNX1 (Homo sapiens)
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Description
The RUNX1 (AML1) transcription factor is a master regulator of hematopoiesis (Ichikawa et al. 2004) that is frequently translocated in acute myeloid leukemia (AML), resulting in formation of fusion proteins with altered transactivation profiles (Lam and Zhang 2012, Ichikawa et al. 2013). In addition to RUNX1, its heterodimerization partner CBFB is also frequently mutated in AML (Shigesada et al. 2004, Mangan and Speck 2011).
The core domain of CBFB binds to the Runt domain of RUNX1, resulting in formation of the RUNX1:CBFB heterodimer. CBFB does not interact with DNA directly. The Runt domain of RUNX1 mediated both DNA binding and heterodimerization with CBFB (Tahirov et al. 2001), while RUNX1 regions that flank the Runt domain are involved in transactivation (reviewed in Zhang et al. 2003) and negative regulation (autoinhibition). CBFB facilitates RUNX1 binding to DNA by stabilizing Runt domain regions that interact with the major and minor grooves of the DNA (Tahirov et al. 2001, Backstrom et al. 2002, Bartfeld et al. 2002). The transactivation domain of RUNX1 is located C-terminally to the Runt domain and is followed by the negative regulatory domain. Autoinhibiton of RUNX1 is relieved by interaction with CBFB (Kanno et al. 1998).
Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs) (Zhao et al. 2014), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid (Friedman 2009) and megakaryocytic progenitors (Goldfarb 2009), regulatory T lymphocytes (Wong et al. 2011) and B lymphocytes (Boller and Grosschedl 2014).
RUNX1 binds to promoters of many genes involved in ribosomal biogenesis (Ribi) and is thought to stimulate their transcription. RUNX1 loss-of-function decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells (HSPCs). RUNX1 loss-of-function is therefore associated with a slow growth, but at the same time it results in reduced apoptosis and increases resistance of cells to genotoxic and endoplasmic reticulum stress, conferring an overall selective advantage to RUNX1 deficient HSPCs (Cai et al. 2015).
RUNX1 is implicated as a tumor suppressor in breast cancer. RUNX1 forms a complex with the activated estrogen receptor alpha (ESR1) and regulates expression of estrogen-responsive genes (Chimge and Frenkel 2013).
RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion (Keita et al. 2013).
RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage (Wu et al. 2013).
RUNX1 is needed for the maintenance of skeletal musculature (Wang et al. 2005).
During mouse embryonic development, Runx1 is expressed in most nociceptive sensory neurons, which are involved in the perception of pain. In adult mice, Runx1 is expressed only in nociceptive sensory neurons that express the Ret receptor and is involved in regulation of expression of genes encoding ion channels (sodium-gated, ATP-gated and hydrogen ion-gated) and receptors (thermal receptors, opioid receptor MOR and the Mrgpr class of G protein coupled receptors). Mice lacking Runx1 show defective perception of thermal and neuropathic pain (Chen CL et al. 2006). Runx1 is thought to activate the neuronal differentiation of nociceptive dorsal root ganglion cells during embryonal development possibly through repression of Hes1 expression (Kobayashi et al. 2012). In chick and mouse embryos, Runx1 expression is restricted to the dorso-medial domain of the dorsal root ganglion, to TrkA-positive cutaneous sensory neurons. Runx3 expression in chick and mouse embryos is restricted to ventro-lateral domain of the dorsal root ganglion, to TrkC-positive proprioceptive neurons (Chen AI et al. 2006, Kramer et al. 2006). RUNX1 mediated regulation of neuronally expressed genes will be annotated when mechanistic details become available. View original pathway at Reactome.
The core domain of CBFB binds to the Runt domain of RUNX1, resulting in formation of the RUNX1:CBFB heterodimer. CBFB does not interact with DNA directly. The Runt domain of RUNX1 mediated both DNA binding and heterodimerization with CBFB (Tahirov et al. 2001), while RUNX1 regions that flank the Runt domain are involved in transactivation (reviewed in Zhang et al. 2003) and negative regulation (autoinhibition). CBFB facilitates RUNX1 binding to DNA by stabilizing Runt domain regions that interact with the major and minor grooves of the DNA (Tahirov et al. 2001, Backstrom et al. 2002, Bartfeld et al. 2002). The transactivation domain of RUNX1 is located C-terminally to the Runt domain and is followed by the negative regulatory domain. Autoinhibiton of RUNX1 is relieved by interaction with CBFB (Kanno et al. 1998).
Transcriptional targets of the RUNX1:CBFB complex involve genes that regulate self-renewal of hematopoietic stem cells (HSCs) (Zhao et al. 2014), as well as commitment and differentiation of many hematopoietic progenitors, including myeloid (Friedman 2009) and megakaryocytic progenitors (Goldfarb 2009), regulatory T lymphocytes (Wong et al. 2011) and B lymphocytes (Boller and Grosschedl 2014).
RUNX1 binds to promoters of many genes involved in ribosomal biogenesis (Ribi) and is thought to stimulate their transcription. RUNX1 loss-of-function decreases ribosome biogenesis and translation in hematopoietic stem and progenitor cells (HSPCs). RUNX1 loss-of-function is therefore associated with a slow growth, but at the same time it results in reduced apoptosis and increases resistance of cells to genotoxic and endoplasmic reticulum stress, conferring an overall selective advantage to RUNX1 deficient HSPCs (Cai et al. 2015).
RUNX1 is implicated as a tumor suppressor in breast cancer. RUNX1 forms a complex with the activated estrogen receptor alpha (ESR1) and regulates expression of estrogen-responsive genes (Chimge and Frenkel 2013).
RUNX1 is overexpressed in epithelial ovarian carcinoma where it may contribute to cell proliferation, migration and invasion (Keita et al. 2013).
RUNX1 may cooperate with TP53 in transcriptional activation of TP53 target genes upon DNA damage (Wu et al. 2013).
RUNX1 is needed for the maintenance of skeletal musculature (Wang et al. 2005).
During mouse embryonic development, Runx1 is expressed in most nociceptive sensory neurons, which are involved in the perception of pain. In adult mice, Runx1 is expressed only in nociceptive sensory neurons that express the Ret receptor and is involved in regulation of expression of genes encoding ion channels (sodium-gated, ATP-gated and hydrogen ion-gated) and receptors (thermal receptors, opioid receptor MOR and the Mrgpr class of G protein coupled receptors). Mice lacking Runx1 show defective perception of thermal and neuropathic pain (Chen CL et al. 2006). Runx1 is thought to activate the neuronal differentiation of nociceptive dorsal root ganglion cells during embryonal development possibly through repression of Hes1 expression (Kobayashi et al. 2012). In chick and mouse embryos, Runx1 expression is restricted to the dorso-medial domain of the dorsal root ganglion, to TrkA-positive cutaneous sensory neurons. Runx3 expression in chick and mouse embryos is restricted to ventro-lateral domain of the dorsal root ganglion, to TrkC-positive proprioceptive neurons (Chen AI et al. 2006, Kramer et al. 2006). RUNX1 mediated regulation of neuronally expressed genes will be annotated when mechanistic details become available. View original pathway at Reactome.
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beta-catenin by the
destruction complexcontrol the development of regulatory T
lymphocytes (Tregs)The RUNX1:CBFB complex directly stimulates transcription of the CR1 gene, encoding Complement receptor type 1 (CD35) (Kim et al. 1999, Rho et al. 2002). Expression of CR1 on the surface of activated T cells contributes to generation of Tregs (Torok et al. 2015).
genes involved in megakaryocyte differentiation and
platelet functionMegakaryocytic promoters regulated by the described RUNX1:CBFB activating and repressing complexes include ITGA2B, GP1BA, THBS1 and MIR27A (Herglotz et al. 2013). ITGA2B is only expressed in maturing megakaryocytes and platelets and is involved in platelet aggregation (Block and Poncz 1995). GP1BA is expressed at the cell surface membrane of maturing megakaryocytes and platelets and participates in formation of platelet plugs (Cauwenberghs et al. 2000, Jilma-Stohlawetz et al. 2003, Debili et al. 1990). THBS1 homotrimers contribute to stabilization of the platelet aggregate (Bonnefoy and Hoylaerts 2008). MIR27A is a negative regulator of RUNX1 mRNA translation and may be involved in erythroid/megakaryocytic lineage determination (Ben-Ami et al. 2009).
The RUNX1:CBFB complex stimulates transcription of the PF4 gene, encoding a component of platelet alpha granules (Aneja et al. 2011), the NR4A3 gene, associated with the familial platelet disorder (FPD) (Bluteau et al. 2011), the PRKCQ gene, associated with inherited thrombocytopenia (Jalagadugula et al. 2011), the MYL9 gene, involved in thrombopoiesis (Jalagadugula et al. 2010), and the NFE2 gene, a regulator of erythroid and megakaryocytic maturation and differentiation (Wang et al. 2010).
Expression and
ActivityRUNX1 mRNAs transcribed from alternative promoters differ in their 5'UTRs and splicing isoforms of RUNX1 have also been described. The function of alternative splice isoforms and alternative 5'UTRs has not been fully elucidated (Challen and Goodell 2010, Komeno et al. 2014).
During zebrafish hematopoiesis, RUNX1 expression increases in response to NOTCH signaling, but direct transcriptional regulation of RUNX1 by NOTCH has not been demonstrated (Burns et al. 2005). RUNX1 transcription also increases in response to WNT signaling. BothTCF7 and TCF4 bind the RUNX1 promoter (Wu et al. 2012, Hoverter et al. 2012), and RUNX1 transcription driven by the TCF binding element (TBE) in response to WNT3A treatment is inhibited by the dominant-negative mutant of TCF4 (Medina et al. 2016). In developing mouse ovary, Runx1 expression is positively regulated by Wnt4 signaling (Naillat et al. 2015).
Studies in mouse hematopoietic stem and progenitor cells imply that RUNX1 may be a direct transcriptional target of HOXB4 (Oshima et al. 2011).
Conserved cis-regulatory elements were recently identified in intron 5 of RUNX1. The RUNX1 breakpoints observed in acute myeloid leukemia (AML) with translocation (8;21), which result in expression of a fusion RUNX1-ETO protein, cluster in intron 5, in proximity to these not yet fully characterized cis regulatory elements (Rebolledo-Jaramillo et al. 2014).
At the level of translation, RUNX1 expression is regulated by various microRNAs which bind to the 3'UTR of RUNX1 mRNA and inhibit its translation through endonucleolytic and/or nonendonucleolytic mechanisms. MicroRNAs that target RUNX1 include miR-378 (Browne et al. 2016), miR-302b (Ge et al. 2014), miR-18a (Miao et al. 2015), miR-675 (Zhuang et al. 2014), miR-27a (Ben-Ami et al. 2009), miR-17, miR-20a, miR106 (Fontana et al. 2007) and miR-215 (Li et al. 2016).
At the posttranslational level, RUNX1 activity is regulated by postranslational modifications and binding to co-factors. SRC family kinases phosphorylate RUNX1 on multiple tyrosine residues in the negative regulatory domain, involved in autoinhibition of RUNX1. RUNX1 tyrosine phosphorylation correlates with reduced binding of RUNX1 to GATA1 and increased binding of RUNX1 to the SWI/SNF complex, leading to inhibition of RUNX1-mediated differentiation of T-cells and megakaryocytes. SHP2 (PTPN11) tyrosine phosphatase binds to RUNX1 and dephosphorylates it (Huang et al. 2012).
Formation of the complex with CBFB is necessary for the transcriptional activity of RUNX1 (Wang et al. 1996). Binding of CCND3 and probably other two cyclin D family members, CCND1 and CCND2, to RUNX1 inhibits its association with CBFB (Peterson et al. 2005), while binding to CDK6 interferes with binding of RUNX1 to DNA without affecting formation of the RUNX1:CBFB complex. Binding of RUNX1 to PML plays a role in subnuclear targeting of RUNX1 (Nguyen et al. 2005).
RUNX1 activity and protein levels vary during the cell cycle. RUNX1 protein levels increase from G1 to S and from S to G2 phases, with no increase in RUNX1 mRNA levels. CDK1-mediated phosphorylation of RUNX1 at the G2/M transition is implicated in reduction of RUNX1 transactivation potency and may promote RUNX1 protein degradation by the anaphase promoting complex (reviewed by Friedman 2009).
NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.
NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2 or MAML3; possibly also MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters.
RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA) (Kammerer et al. 2013), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1) (Zhang et al. 2012), NKX3-2 (BAPX1) (Tribioli and Lufkin 1999, Lengner et al. 2005), DLX5 (Robledo et al. 2002, Lee et al. 2005) and MSX2 (Lee et al. 2005). RUNX2 can autoregulate, by directly inhibiting its own transcription (Drissi et al. 2000). Several E3 ubiquitin ligases target RUNX2 for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016). Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 (Bialek et al. 2004) and RB1 (Thomas et al. 2001).
RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 (Li et al. 2016) and the ITGBL1 gene, encoding Integrin beta like protein 1 (Li et al. 2015). RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 (Pande et al. 2013). RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells (Tandon et al. 2014).
RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).
For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015.
Annotated Interactions
The AXIN1 gene expression is stimulated by cooperative binding of RUNX1 and estrogen receptor alpha (ESR1) to adjacent RUNX1 binding sites and estrogen response elements in the second intron of AXIN1 (Chimge et al. 2016).
ITCH is an important regulator of hematopoietic stem cell (HSC) function and homeostasis. ITCH reduces the proliferation rate of HSCs by downregulating NOTCH1 (Rathinam et al. 2011).