Regulation of RUNX1 Expression and Activity

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R-HSA-8934593
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Homo sapiens
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At the level of transcription, expression of the RUNX1 transcription factor is regulated by two alternative promoters: a distal promoter, P1, and a proximal promoter, P2. P1 is more than 7 kb upstream of P2 (Ghozi et al. 1996). In mice, the Runx1 gene is preferentially transcribed from the proximal P2 promoter during generation of hematopoietic cells from hemogenic endothelium. In fully committed hematopoietic progenitors, the Runx1 gene is preferentially transcribed from the distal P1 promoter (Sroczynska et al. 2009, Bee et al. 2010). In human T cells, RUNX1 is preferentially transcribed from P1 throughout development, while developing natural killer cells transcribe RUNX1 predominantly from P2. Developing B cells transcribe low levels of RUNX1 from both promoters (Telfer and Rothenberg 2001).
RUNX1 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).

Literature References
PubMed ID Title Journal Year
24388988 The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1

Zhuang, M, Gao, W, Xu, J, Wang, P, Shu, Y

Biochem. Biophys. Res. Commun. 2014
26716895 miR-215 promotes malignant progression of gastric cancer by targeting RUNX1

Li, N, Zhang, QY, Zou, JL, Li, ZW, Tian, TT, Dong, B, Liu, XJ, Ge, S, Zhu, Y, Gao, J, Shen, L

Oncotarget 2016
20206228 Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cells

Challen, GA, Goodell, MA

Exp. Hematol. 2010
25562167 MicroRNA-302b suppresses human epithelial ovarian cancer cell growth by targeting RUNX1

Ge, T, Yin, M, Yang, M, Liu, T, Lou, G

Cell. Physiol. Biochem. 2014
25452107 MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5

Miao, YS, Zhao, YY, Zhao, LN, Wang, P, Liu, YH, Ma, J, Xue, YX

Cell. Signal. 2015
24771859 Runx1 exon 6-related alternative splicing isoforms differentially regulate hematopoiesis in mice

Komeno, Y, Yan, M, Matsuura, S, Lam, K, Lo, MC, Huang, YJ, Tenen, DG, Downing, JR, Zhang, DE

Blood 2014
19235904 Cell cycle and developmental control of hematopoiesis by Runx1

Friedman, AD

J. Cell. Physiol. 2009
20139099 Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis

Bee, T, Swiers, G, Muroi, S, Pozner, A, Nottingham, W, Santos, AC, Li, PS, Taniuchi, I, de Bruijn, MF

Blood 2010
22778133 A WNT/p21 circuit directed by the C-clamp, a sequence-specific DNA binding domain in TCFs

Hoverter, NP, Ting, JH, Sundaresh, S, Baldi, P, Waterman, ML

Mol. Cell. Biol. 2012
17589498 MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation

Fontana, L, Pelosi, E, Greco, P, Racanicchi, S, Testa, U, Liuzzi, F, Croce, CM, Brunetti, E, Grignani, F, Peschle, C

Nat. Cell Biol. 2007
26580584 Alternative RUNX1 Promoter Regulation by Wnt/β-Catenin Signaling in Leukemia Cells and Human Hematopoietic Progenitors

Medina, MA, Ugarte, GD, Vargas, MF, Avila, ME, Necuñir, D, Elorza, AA, Gutiérrez, SE, De Ferrari, GV

J. Cell. Physiol. 2016
8700862 Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions

Ghozi, MC, Bernstein, Y, Negreanu, V, Levanon, D, Groner, Y

Proc. Natl. Acad. Sci. U.S.A. 1996
16166372 Hematopoietic stem cell fate is established by the Notch-Runx pathway

Burns, CE, Traver, D, Mayhall, E, Shepard, JL, Zon, LI

Genes Dev. 2005
15331439 Physical and functional link of the leukemia-associated factors AML1 and PML

Nguyen, LA, Pandolfi, PP, Aikawa, Y, Tagata, Y, Ohki, M, Kitabayashi, I

Blood 2005
22759635 A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation

Huang, H, Woo, AJ, Waldon, Z, Schindler, Y, Moran, TB, Zhu, HH, Feng, GS, Steen, H, Cantor, AB

Genes Dev. 2012
26749280 MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

Browne, G, Dragon, JA, Hong, D, Messier, TL, Gordon, JA, Farina, NH, Boyd, JR, VanOudenhove, JJ, Perez, AW, Zaidi, SK, Stein, JL, Stein, GS, Lian, JB

Tumour Biol. 2016
21343615 Genome-wide analysis of target genes regulated by HoxB4 in hematopoietic stem and progenitor cells developing from embryonic stem cells

Oshima, M, Endoh, M, Endo, TA, Toyoda, T, Nakajima-Takagi, Y, Sugiyama, F, Koseki, H, Kyba, M, Iwama, A, Osawa, M

Blood 2011
19114653 A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis

Ben-Ami, O, Pencovich, N, Lotem, J, Levanon, D, Groner, Y

Proc. Natl. Acad. Sci. U.S.A. 2009
25645944 Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary

Naillat, F, Yan, W, Karjalainen, R, Liakhovitskaia, A, Samoylenko, A, Xu, Q, Sun, Z, Shen, B, Medvinsky, A, Quaggin, S, Vainio, SJ

Exp. Cell Res. 2015
22412390 Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line

Wu, JQ, Seay, M, Schulz, VP, Hariharan, M, Tuck, D, Lian, J, Du, J, Shi, M, Ye, Z, Gerstein, M, Snyder, MP, Weissman, S

PLoS Genet. 2012
19858498 The differential activities of Runx1 promoters define milestones during embryonic hematopoiesis

Sroczynska, P, Lancrin, C, Kouskoff, V, Lacaud, G

Blood 2009
11203699 Expression and function of a stem cell promoter for the murine CBFalpha2 gene: distinct roles and regulation in natural killer and T cell development

Telfer, JC, Rothenberg, EV

Dev. Biol. 2001
8929538 The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo

Wang, Q, Stacy, T, Miller, JD, Lewis, AF, Gu, TL, Huang, X, Bushweller, JH, Bories, JC, Alt, FW, Ryan, G, Liu, PP, Wynshaw-Boris, A, Binder, M, Marín-Padilla, M, Sharpe, AH, Speck, NA

Cell 1996
16287839 The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3

Peterson, LF, Boyapati, A, Ranganathan, V, Iwama, A, Tenen, DG, Tsai, S, Zhang, DE

Mol. Cell. Biol. 2005
24655352 Cis-regulatory elements are harbored in Intron5 of the RUNX1 gene

Rebolledo-Jaramillo, B, Alarcon, RA, Fernandez, VI, Gutiérrez, SE

BMC Genomics 2014
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