BioPAX pathway converted from "Regulation of RUNX1 Expression and Activity" in the Reactome database.Regulation of RUNX1 Expression and ActivityRegulation of RUNX1 Expression and ActivityThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>CDK6 binds RUNX1CDK6 binds RUNX1This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Converted from EntitySet in ReactomeReactome DB_ID: 106492701nucleoplasmGO0005654RUNX1,RUNX1:CBFB [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityRUNX1 [nucleoplasm]Reactomehttp://www.reactome.orgUniProtG5EFQ5Reactome DB_ID: 106492681UniProt:Q9XTR1Caenorhabditis elegansNCBI Taxonomy6239UniProtQ9XTR1Chain Coordinates1EQUAL326EQUALReactome DB_ID: 106492721RUNX1,RUNX1:CBFB:CDK6 [nucleoplasm]RUNX1,RUNX1:CBFB:CDK6Converted from EntitySet in ReactomeReactome DB_ID: 106492701Reactome DB_ID: 1064926811EQUAL326EQUALReactome Database ID Release 7010649272Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649272ReactomeR-CEL-89388541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8938854.1Reactome Database ID Release 7010649274Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649274ReactomeR-CEL-89388531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8938853.1CDK6 binds to the Runt domain of RUNX1 and interferes with RUNX1 binding to DNA and transcription co-factors. Formation of the RUNX1:CBFB complex does not affect the ability of CDK6 to interact with RUNX1. Neither the catalytic activity nor the cyclin-binding activity of CDK6 are required for its association with RUNX1 (Fujimoto et al. 2007).17431401Pubmed2007Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interactionFujimoto, TAnderson, KJacobsen, S E WNishikawa, S-INerlov, CEMBO J. 26:2361-70inferred by electronic annotationIEAGOIEAPML binds RUNX1PML binds RUNX1This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 106471021UniProt:G5EFQ51EQUAL453EQUALConverted from EntitySet in ReactomeReactome DB_ID: 106260171Homologues of PML [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPML [nucleoplasm]PML [nucleoplasm]UniProtG5ED20UniProtH2L0K3Reactome DB_ID: 106492761RUNX1:PML [nucleoplasm]RUNX1:PMLReactome DB_ID: 1064710211EQUAL453EQUALConverted from EntitySet in ReactomeReactome DB_ID: 106260171Reactome Database ID Release 7010649276Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649276ReactomeR-CEL-89388851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8938885.1Reactome Database ID Release 7010649278Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649278ReactomeR-CEL-89388871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8938887.1RUNX1 interacts with PML, and the interaction involves the C-terminus of PML and the C-terminus of RUNX1. PML targets RUNX1 to nuclear bodies, which may be important for activation of some RUNX1 target genes, such as CSF2 (GM-CSF) (Nguyen et al. 2005).15331439Pubmed2005Physical and functional link of the leukemia-associated factors AML1 and PMLNguyen, Lan AnhPandolfi, Pier PaoloAikawa, YukikoTagata, YusukeOhki, MisaoKitabayashi, IssayBlood 105:292-300inferred by electronic annotationIEAGOIEACBFB binds RUNX1CBFB binds RUNX1This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 106471001UniProt:Q95ZL9UniProtQ95ZL91EQUAL182EQUALReactome DB_ID: 1064710211EQUAL453EQUALReactome DB_ID: 106471041RUNX1:CBFB [nucleoplasm]RUNX1:CBFBReactome DB_ID: 1064710011EQUAL182EQUALReactome DB_ID: 1064710211EQUAL453EQUALReactome Database ID Release 7010647104Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10647104ReactomeR-CEL-88653301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8865330.1Reactome Database ID Release 7010647106Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10647106ReactomeR-CEL-88653201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8865320.1The heterodimerization domain of CBFB binds to the Runt domain of RUNX1 (AML1) to form a RUNX1:CBFB heterodimer (Warren et al. 2000, Lukasik et al. 2002). Formation of the RUNX1:CBFB heterodimer was first demonstrated in Drosophila (Ogawa et al. 1993). While RUNX1 is the DNA binding subunit, the presence of CBFB is necessary for the transcriptional activity of the RUNX1:CBFB complex, based on knockout mouse studies (Wang et al. 1996).<br>The RUNX1:CBFB transcription complex is essential for hematopoiesis (Warren et al. 2000).<p>Both CBFB and RUNX1 are subject to frequent mutations in leukemia (Ustun and Marcucci 2015).8386878Pubmed1993Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alphaOgawa, EInuzuka, MMaruyama, MSatake, MNaito-Fujimoto, MIto, YShigesada, KVirology 194:314-3125635758Pubmed2015Emerging diagnostic and therapeutic approaches in core binding factor acute myeloid leukaemiaUstun, CelalettinMarcucci, GuidoCurr. Opin. Hematol. 22:85-9112172539Pubmed2002Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesisLukasik, Stephen MZhang, LinaCorpora, TakeshiTomanicek, SarahLi, YuanhongKundu, MondiraHartman, KariLiu, P PaulLaue, Thomas MBiltonen, Rodney LSpeck, Nancy ABushweller, John HNat. Struct. Biol. 9:674-910856244Pubmed2000Structural basis for the heterodimeric interaction between the acute leukaemia-associated transcription factors AML1 and CBFbetaWarren, A JBravo, JWilliams, R LRabbitts, T HEMBO J. 19:3004-158929538Pubmed1996The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivoWang, QStacy, TMiller, J DLewis, A FGu, T LHuang, XBushweller, J HBories, J CAlt, F WRyan, GLiu, P PWynshaw-Boris, ABinder, MMarín-Padilla, MSharpe, A HSpeck, N ACell 87:697-708inferred by electronic annotationIEAGOIEAReactome Database ID Release 7010655206Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10655206ReactomeR-CEL-89345931Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8934593.1At 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).<br>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).<br>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).<br>Studies in mouse hematopoietic stem and progenitor cells imply that RUNX1 may be a direct transcriptional target of HOXB4 (Oshima et al. 2011).<br>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).<br>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).<br>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).<br>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).<br>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).22412390Pubmed2012Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell lineWu, Jia QianSeay, MontrellSchulz, Vincent PHariharan, ManojTuck, DavidLian, JinDu, JiangShi, MinyiYe, ZhijiaGerstein, MarkSnyder, Michael PWeissman, ShermanPLoS Genet. 8:e100256511203699Pubmed2001Expression and function of a stem cell promoter for the murine CBFalpha2 gene: distinct roles and regulation in natural killer and T cell developmentTelfer, J CRothenberg, E VDev. Biol. 229:363-8221343615Pubmed2011Genome-wide analysis of target genes regulated by HoxB4 in hematopoietic stem and progenitor cells developing from embryonic stem cellsOshima, MotohikoEndoh, MitsuhiroEndo, Takaho AToyoda, TetsuroNakajima-Takagi, YaekoSugiyama, FumihiroKoseki, HaruhikoKyba, MichaelIwama, AtsushiOsawa, MitsujiroBlood 117:e142-5024388988Pubmed2014The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1Zhuang, MingGao, WenXu, JingWang, PingShu, YongqianBiochem. Biophys. Res. Commun. 448:315-2222759635Pubmed2012A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiationHuang, HuiWoo, Andrew JWaldon, ZacharySchindler, YochevedMoran, Tyler BZhu, Helen HFeng, Gen-ShengSteen, HannoCantor, Alan BGenes Dev. 26:1587-60119235904Pubmed2009Cell cycle and developmental control of hematopoiesis by Runx1Friedman, Alan DJ. Cell. Physiol. 219:520-420206228Pubmed2010Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cellsChallen, Grant AGoodell, Margaret AExp. Hematol. 38:403-1626580584Pubmed2016Alternative RUNX1 Promoter Regulation by Wnt/β-Catenin Signaling in Leukemia Cells and Human Hematopoietic ProgenitorsMedina, Matías AUgarte, Giorgia DVargas, Macarena FAvila, Miguel ENecuñir, DavidElorza, Alvaro AGutiérrez, Soraya EDe Ferrari, Giancarlo VJ. Cell. Physiol. 231:1460-720139099Pubmed2010Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesisBee, ThomasSwiers, GemmaMuroi, SawakoPozner, AmirNottingham, WadeSantos, Ana CristinaLi, Pik-ShanTaniuchi, Ichirode Bruijn, Marella F T RBlood 115:3042-5025562167Pubmed2014MicroRNA-302b suppresses human epithelial ovarian cancer cell growth by targeting RUNX1Ge, TingtingYin, MingzhuYang, MengLiu, TianboLou, GeCell. Physiol. Biochem. 34:2209-2024655352Pubmed2014Cis-regulatory elements are harbored in Intron5 of the RUNX1 geneRebolledo-Jaramillo, BorisAlarcon, Ricardo AFernandez, Valentina IGutiérrez, Soraya EBMC Genomics 15:22525645944Pubmed2015Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovaryNaillat, FlorenceYan, WenyingKarjalainen, RiikkaLiakhovitskaia, AnnaSamoylenko, AnatolyXu, QiSun, ZhandongShen, BairongMedvinsky, AlexanderQuaggin, SusanVainio, Seppo JExp. Cell Res. 332:163-7819858498Pubmed2009The differential activities of Runx1 promoters define milestones during embryonic hematopoiesisSroczynska, PatrycjaLancrin, ChristopheKouskoff, ValerieLacaud, GeorgesBlood 114:5279-8916287839Pubmed2005The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3Peterson, Luke FBoyapati, AnitaRanganathan, VelvizhiIwama, AtsushiTenen, Daniel GTsai, SchickwannZhang, Dong-ErMol. Cell. Biol. 25:10205-1919114653Pubmed2009A regulatory interplay between miR-27a and Runx1 during megakaryopoiesisBen-Ami, OrenPencovich, NivLotem, JosephLevanon, DitsaGroner, YoramProc. Natl. Acad. Sci. U.S.A. 106:238-4322778133Pubmed2012A WNT/p21 circuit directed by the C-clamp, a sequence-specific DNA binding domain in TCFsHoverter, Nate PTing, Ju-HuiSundaresh, SumanBaldi, PierreWaterman, Marian LMol. Cell. Biol. 32:3648-628700862Pubmed1996Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regionsGhozi, M CBernstein, YNegreanu, VLevanon, DGroner, YProc. Natl. Acad. Sci. U.S.A. 93:1935-4024771859Pubmed2014Runx1 exon 6-related alternative splicing isoforms differentially regulate hematopoiesis in miceKomeno, YukikoYan, MingMatsuura, ShinobuLam, KentsonLo, Miao-ChiaHuang, Yi-JouTenen, Daniel GDowning, James RZhang, Dong-ErBlood 123:3760-926716895Pubmed2016miR-215 promotes malignant progression of gastric cancer by targeting RUNX1Li, NaZhang, Qi-YueZou, Jian-LingLi, Zhong-WuTian, Tian-TianDong, BinLiu, Xi-JuanGe, SaiZhu, YanGao, JingShen, LinOncotarget 7:4817-2826749280Pubmed2016MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cellsBrowne, GillianDragon, Julie AHong, DeliMessier, Terri LGordon, Jonathan A RFarina, Nicholas HBoyd, Joseph RVanOudenhove, Jennifer JPerez, Andrew WZaidi, Sayyed KStein, Janet LStein, Gary SLian, Jane BTumour Biol.17589498Pubmed2007MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulationFontana, LauraPelosi, ElviraGreco, PaoloRacanicchi, SerenaTesta, UgoLiuzzi, FrancescaCroce, CMBrunetti, ErcoleGrignani, FrancescoPeschle, CesareNat. Cell Biol. 9:775-8716166372Pubmed2005Hematopoietic stem cell fate is established by the Notch-Runx pathwayBurns, Caroline ErterTraver, DavidMayhall, ElizabethShepard, Jennifer LZon, Leonard IGenes Dev. 19:2331-4225452107Pubmed2015MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5Miao, Yin-ShaZhao, Ying-YuZhao, Li-NiWang, PingLiu, Yun-HuiMa, JunXue, Yi-XueCell. Signal. 27:156-67inferred by electronic annotationIEAGOIEA