Regulation of RUNX1 Expression and Activity (Homo sapiens)

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1, 6, 7, 12-14, 16...48481, 6, 25, 28, 47...6331353150121248283, 9, 224725231212nucleoplasmcytosolmiR-20aNonendonucleolyticRISCAGO2 MOV10 EIF2C1 EIF2C4 RUNX1:PMLRUNX1 mRNA:miR-27aNonendonucleolyticRISCmiR-18a RISCCBFB TNRC6A miR-18a RUNX1 mRNA EIF2C4 PTPN11EIF2C1 TNRC6A miR-20a TNRC6A EIF2C4 MOV10 EIF2C3 CBFB RUNX1 miR-17 TNRC6A EIF2C4 miR-302b CBFB miR-378NonendonucleolyticRISCCDK6 EIF2C3 EIF2C4 EIF2C1 miR-27a EIF2C4 RUNX1 TNRC6B TNRC6C EIF2C1 TNRC6C TNRC6B RUNX1,RUNX1:CBFBRUNX1 mRNA TNRC6B EIF2C4 MOV10 EIF2C1 EIF2C3 miR-302b AGO2 RUNX1 p-7Y-RUNX1EIF2C4 EIF2C4 RUNX1 mRNA:miR-20aNonendonucleolyticRISCEIF2C4 EIF2C1 EIF2C4 EIF2C3 miR-675 RISCRUNX1:CCND3,(CCND1,CCND2)RUNX1 mRNA EIF2C1 MOV10 EIF2C1 RUNX1 mRNA p-Y419-SRCmiR-215 CCND1 EIF2C4 MOV10 EIF2C3 EIF2C3 CBFBTNRC6B EIF2C4 CCND3,(CCND1,CCND2)miR-106a RUNX1 mRNA MOV10 RUNX1 mRNA EIF2C3 CCND2 AGO2 EIF2C3 TNRC6B miR-106aNonendonucleolyticRISCRUNX1 mRNA EIF2C1 TNRC6B ATPTNRC6B miR-302b RISCEIF2C3 TNRC6A TNRC6B RUNX1 mRNA:miR-378NonendonucleolyticRISClncRNA H19TNRC6A miR-378 TNRC6A miR-20a EIF2C4 MOV10 AGO2 CDK6TNRC6C TNRC6C TNRC6C AGO2 AGO2 EIF2C1 MOV10 TNRC6A RUNX1TNRC6C TNRC6C AGO2 TNRC6A EIF2C1 EIF2C1 TNRC6C TNRC6C TNRC6B p-Y419-SRC Transcriptionalregulation by RUNX1EIF2C4 EIF2C3 TNRC6A TNRC6A TNRC6A RUNX1 TNRC6C MOV10 PML ADPTNRC6A PMLEIF2C3 TNRC6A miR-106a RUNX1 mRNA:miR-106aNonendonucleolyticRISCTNRC6C miR-215 RISCTNRC6C TNRC6B TNRC6C MOV10 miR-17NonendonucleolyticRISCCCND2 MOV10 MOV10 RUNX1 mRNAEIF2C1 PTPN11 miR-18a RUNX1 mRNA:miR-302bRISCmiR-215 p-7Y-RUNX1:PTPN11miR-675 TNRC6C MOV10 TNRC6B miR-675 MOV10 EIF2C3 MOV10 H2OTNRC6B p-Y419-SRC:RUNX1miR-17 TNRC6A miR-27aNonendonucleolyticRISCEIF2C1 TNRC6B CCND3 PiRUNX1 mRNA:miR-17NonendonucleolyticRISCp-7Y-RUNX1 EIF2C3 CCND1 MOV10 EIF2C4 EIF2C1 TNRC6B RUNX1 EIF2C3 TNRC6A TNRC6B EIF2C1 miR-378 AGO2 RUNX1 mRNA EIF2C4 miR-27a EIF2C4 EIF2C3 MOV10 EIF2C3 RUNX1 mRNA TNRC6C EIF2C1 MOV10 TNRC6B TNRC6A RUNX1,RUNX1:CBFB:CDK6EIF2C3 TNRC6C CCND3 TNRC6C RUNX1:CBFBTNRC6B TNRC6B RUNX1 mRNA:miR-215RISCRUNX1 RUNX1 mRNA:miR-675RISCTNRC6C TNRC6A RUNX1 mRNA:miR-18aRISCEIF2C1 EIF2C3 35471212136485028254830, 4630, 462, 4, 5, 8, 10...314833


Description

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). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8934593
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101560view11:43, 1 November 2018ReactomeTeamreactome version 66
101096view21:26, 31 October 2018ReactomeTeamreactome version 65
100625view20:00, 31 October 2018ReactomeTeamreactome version 64
100176view16:45, 31 October 2018ReactomeTeamreactome version 63
99726view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99300view12:46, 31 October 2018ReactomeTeamreactome version 62
93612view11:28, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AGO2 ProteinQ9UKV8 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CBFB ProteinQ13951 (Uniprot-TrEMBL)
CBFBProteinQ13951 (Uniprot-TrEMBL)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCND2 ProteinP30279 (Uniprot-TrEMBL)
CCND3 ProteinP30281 (Uniprot-TrEMBL)
CCND3,(CCND1,CCND2)ComplexR-HSA-8938866 (Reactome)
CDK6 ProteinQ00534 (Uniprot-TrEMBL)
CDK6ProteinQ00534 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
PML ProteinP29590 (Uniprot-TrEMBL)
PMLProteinP29590 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RUNX1 ProteinQ01196 (Uniprot-TrEMBL)
RUNX1 mRNA ProteinENST00000344691 (Ensembl)
RUNX1 mRNA:miR-106a

Nonendonucleolytic

RISC
ComplexR-HSA-8938506 (Reactome)
RUNX1 mRNA:miR-17

Nonendonucleolytic

RISC
ComplexR-HSA-8938450 (Reactome)
RUNX1 mRNA:miR-18a RISCComplexR-HSA-8935945 (Reactome)
RUNX1 mRNA:miR-20a

Nonendonucleolytic

RISC
ComplexR-HSA-8938485 (Reactome)
RUNX1 mRNA:miR-215 RISCComplexR-HSA-8939132 (Reactome)
RUNX1 mRNA:miR-27a

Nonendonucleolytic

RISC
ComplexR-HSA-8937133 (Reactome)
RUNX1 mRNA:miR-302b RISCComplexR-HSA-8935874 (Reactome)
RUNX1 mRNA:miR-378

Nonendonucleolytic

RISC
ComplexR-HSA-8935775 (Reactome)
RUNX1 mRNA:miR-675 RISCComplexR-HSA-8936059 (Reactome)
RUNX1 mRNARnaENST00000344691 (Ensembl)
RUNX1,RUNX1:CBFB:CDK6ComplexR-HSA-8938854 (Reactome)
RUNX1,RUNX1:CBFBComplexR-HSA-8938850 (Reactome)
RUNX1:CBFBComplexR-HSA-8865330 (Reactome)
RUNX1:CCND3,(CCND1,CCND2)ComplexR-HSA-8938868 (Reactome)
RUNX1:PMLComplexR-HSA-8938885 (Reactome)
RUNX1ProteinQ01196 (Uniprot-TrEMBL)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
Transcriptional regulation by RUNX1PathwayR-HSA-8878171 (Reactome) 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.
lncRNA H19RnaENST00000414790 (Ensembl)
miR-106a

Nonendonucleolytic

RISC
ComplexR-HSA-8938500 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
miR-106a ProteinMI0000113 (miRBase mature sequence)
miR-17

Nonendonucleolytic

RISC
ComplexR-HSA-8938444 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
miR-17 ProteinMI0000071 (miRBase mature sequence)
miR-18a ProteinMI0000072 (miRBase mature sequence)
miR-18a RISCComplexR-HSA-8935934 (Reactome)
miR-20a

Nonendonucleolytic

RISC
ComplexR-HSA-8938486 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
miR-20a ProteinMI0000076 (miRBase mature sequence)
miR-215 ProteinMI0000291 (miRBase mature sequence)
miR-215 RISCComplexR-HSA-8939121 (Reactome)
miR-27a

Nonendonucleolytic

RISC
ComplexR-HSA-8937100 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
miR-27a ProteinMI0000085 (miRBase mature sequence)
miR-302b ProteinMI0000772 (miRBase mature sequence)
miR-302b RISCComplexR-HSA-8935858 (Reactome)
miR-378

Nonendonucleolytic

RISC
ComplexR-HSA-8935760 (Reactome) The RNA-induced silencing complex contains an Argonaute (AGO) protein, whose PAZ domain binds the 3' end of the miRNA. The PIWI domain of AGO is responsible for cleavage of target RNAs, that is, RNAs complementary to the miRNA. Only AGO2 (EIF2C2) is capable of cleavage, however. AGO1 (EIF2C1), AGO3 (EIF2C3), and AGO4 (EIF2C4) repress translation of target RNAs by binding without cleavage. In vivo, cleavage by AGO2 and repression of translation by all AGOs require interaction with a TNRC6 protein (GW182 protein) and MOV10. The interaction with TNRC6 proteins is also responsible for localizing the AGO complex to Processing Bodies (P-bodies). Tethering of the C-terminal domain of a TNRC6 protein to a mRNA is sufficient to cause repression of translation.
miR-378 ProteinMI0000786 (miRBase mature sequence)
miR-675 ProteinMI0005416 (miRBase mature sequence)
miR-675 RISCComplexR-HSA-8936051 (Reactome)
p-7Y-RUNX1 ProteinQ01196 (Uniprot-TrEMBL)
p-7Y-RUNX1:PTPN11ComplexR-HSA-8937751 (Reactome)
p-7Y-RUNX1ProteinQ01196 (Uniprot-TrEMBL)
p-Y419-SRC ProteinP12931 (Uniprot-TrEMBL) Active SRC can be found in the nucleus (Paladino et al. 2016). Myristoylation negatively affects SRC nuclear localization (David-Pfeuty et al. 1993).
p-Y419-SRC:RUNX1ComplexR-HSA-8937687 (Reactome)
p-Y419-SRCProteinP12931 (Uniprot-TrEMBL) Active SRC can be found in the nucleus (Paladino et al. 2016). Myristoylation negatively affects SRC nuclear localization (David-Pfeuty et al. 1993).

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8937728 (Reactome)
ATPR-HSA-8937728 (Reactome)
CBFBR-HSA-8865320 (Reactome)
CCND3,(CCND1,CCND2)R-HSA-8938867 (Reactome)
CDK6R-HSA-8938853 (Reactome)
H2OR-HSA-8937767 (Reactome)
PMLR-HSA-8938887 (Reactome)
PTPN11ArrowR-HSA-8937767 (Reactome)
PTPN11R-HSA-8937744 (Reactome)
PiArrowR-HSA-8937767 (Reactome)
R-HSA-8865320 (Reactome) The 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).
The RUNX1:CBFB transcription complex is essential for hematopoiesis (Warren et al. 2000).

Both CBFB and RUNX1 are subject to frequent mutations in leukemia (Ustun and Marcucci 2015).

R-HSA-8935766 (Reactome) The mature microRNA miR-378a-3p, one of the two single strand products derived from microRNA miR-378 encoded by the MIR378 gene locus, binds the 3'UTR of the RUNX1 mRNA. Since miR-378 does not induce RUNX1 mRNA degradation, it is assumed that miR-378 functions as a component of the nonendonucleolytic RISC. Levels of miR-378 are decreased in triple negative breast cancer (Browne et al. 2016).
R-HSA-8935785 (Reactome) Several microRNAs inhibit RUNX1 mRNA translation without affecting RUNX1 mRNA levels and are thus assumed to function as components of the nonendonucleolytic RISC. These microRNAs include miR 17, miR 20a and miR 106a (Fontana et al. 2007), miR 27a (Ben-Ami et al. 2009), miR 378a (Browne et al. 2016). As RUNX1 directly regulates transcription of the MIR27A gene, RUNX1 and MIR27A constitute a negative feedback loop involved in megakaryocyte differentiation and may regulate the switch between megakaryocytic and erythroid lineages (Ben Ami et al. 2009).
Inhibition of RUNX1 mRNA translation by other microRNAs results in decreased RUNX1 mRNA levels and these microRNAs are therefore assumed to function as components of the endonucleolytic RISC but it is possible that they additionally function as components of nonendonucleolytic RISC. MicroRNAs in this group include miR-18a (Miao et al. 2015), miR-215 (Li et al. 2016), miR-302b (Ge et al. 2014) and miR 675 (Zhuang et al. 2014).

MicroRNA miR 215 binding to the 3'UTR of RUNX1 mRNA inhibits RUNX1 mRNA translation and reduces RUNX1 mRNA levels (Li et al. 2016).


R-HSA-8935864 (Reactome) Mature single stranded microRNA miR-302b-3p, one of the two products of miR-302b encoded by the MIR302B gene, binds to the 3'UTR of RUNX1 mRNA, which results in decreased RUNX1 mRNA and protein levels. As it affects RUNX1 mRNA levels, miR-302b is assumed to function as a component of the endonucleolytic RISC, but it is possible that it additionally functions as a component of the nonendonucleolytic RISC. Levels of miR-302b are decreased in epithelial ovarian carcinoma (Ge et al. 2014).
R-HSA-8935930 (Reactome) Mature single stranded microRNA miR-18a-5p, one of the two products of miR-18a, encoded by the MIR18A gene, binds to the 3'UTR of RUNX1 mRNA, resulting in decreased RUNX1 mRNA and protein levels. As it affects RUNX1 mRNA levels, miR-18a is assumed to function as a component of the endonucleolytic RISC, but it is possible that it additionally functions as a component of the nonendonucleolytic RISC (Miao et al. 2015).
R-HSA-8936058 (Reactome) Mature single stranded microRNA miR-675-5p is one of the two products of miR-675, which is produced from a precursor long non-coding RNA H19 (Cai and Cullen 2007). miR-675-5p binds to the 3'UTR of RUNX1 mRNA, resulting in decreased RUNX1 mRNA and protein levels. As it decreases RUNX1 mRNA levels, miR-675 is assumed to function as a component of the endonucleolytic RISC, but it is possible that it additionally functions as a component of the nonendonucleolytic RISC. Levels of miR-675 are increased in gastric cancer (Zhuang et al. 2014).
R-HSA-8936068 (Reactome) A long non-coding RNA (lncRNA) H19, frequently overexpressed in gastric cancer, functions as a precursor (pri-microRNA) in the production of microRNA miR-675 (Cai and Cullen 2007), which targets and downregulates RUNX1 mRNA, thus interfering with RUNX1 transcription (Zhuang et al. 2014).
R-HSA-8937134 (Reactome) MicroRNA miR-27a binds the 3'UTR of the RUNX1 mRNA. As miR-27a inhibits translation of the RUNX1 mRNA without affecting the RUNX1 mRNA stability, miR-27a is assumed to function within the nonendonucleolytic RISC (Ben-Ami et al. 2009).
R-HSA-8937682 (Reactome) Based on studies in mouse megakaryocytes and T cells, RUNX1 forms a complex with SRC in the nucleus (Huang et al. 2012).
R-HSA-8937728 (Reactome) Based on studies in developing mouse megakaryocytes and T cells, SRC phosphorylates RUNX1 at seven tyrosine residues in the negative regulatory domain (Y254, Y258, Y260, Y376, Y379, Y380 and Y387). Endogenous human RUNX1 is tyrosine phosphorylated, and tyrosine residues in murine Runx1 that are phosphorylated by Src are conserved in human RUNX1. SRC-mediated phosphorylation interferes with binding of RUNX1 to GATA1, thus negatively regulating differentiation of hematopoietic progenitors. SRC-mediated phosphorylation promotes association of RUNX1 with the SWI/SNF complex (Huang et al. 2012).
R-HSA-8937744 (Reactome) Based on mouse studies, tyrosine phosphorylated RUNX1 forms a complex with PTPN11 (SHP2) protein tyrosine phosphatase in the nucleus (Huang et al. 2012).
R-HSA-8937767 (Reactome) Based on mouse studies, PTPN11 (SHP2) protein tyrosine phosphatase dephosphorylates SRC-phosphorylated RUNX1 (Huang et al. 2012).
R-HSA-8938440 (Reactome) MicroRNA miR-17 binds the 3' UTR of the RUNX1 mRNA. As miR-17 does not affect RUNX1 mRNA levels, it presumably function as part of the nonendonucleolytic RISC (Fontana et al. 2007).
R-HSA-8938487 (Reactome) MicroRNA miR-20a binds the 3' UTR of the RUNX1 mRNA. As miR-20a does not affect RUNX1 mRNA levels, it presumably function as part of the nonendonucleolytic RISC (Fontana et al. 2007).
R-HSA-8938507 (Reactome) MicroRNA miR-106a binds the 3' UTR of the RUNX1 mRNA. As miR-106a does not affect RUNX1 mRNA levels, it presumably function as part of the nonendonucleolytic RISC (Fontana et al. 2007).
R-HSA-8938853 (Reactome) CDK6 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).
R-HSA-8938867 (Reactome) Cyclin D3 (CCND3) binds to the runt domain and the activation domain (AD) of RUNX1, thus inhibiting RUNX1 association with CBFB and RUNX1 binding to DNA. Based on in vitro studies, cyclins D1 (CCND1) and D2 (CCND2) can also bind to RUNX1 (Peterson et al. 2005).
R-HSA-8938887 (Reactome) RUNX1 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).
R-HSA-8939129 (Reactome) MicroRNA miR-215 binds to the 3'UTR of RUNX1 (Li et al. 2016).
RUNX1 mRNA:miR-106a

Nonendonucleolytic

RISC
ArrowR-HSA-8938507 (Reactome)
RUNX1 mRNA:miR-17

Nonendonucleolytic

RISC
ArrowR-HSA-8938440 (Reactome)
RUNX1 mRNA:miR-18a RISCArrowR-HSA-8935930 (Reactome)
RUNX1 mRNA:miR-18a RISCTBarR-HSA-8935785 (Reactome)
RUNX1 mRNA:miR-20a

Nonendonucleolytic

RISC
ArrowR-HSA-8938487 (Reactome)
RUNX1 mRNA:miR-215 RISCArrowR-HSA-8939129 (Reactome)
RUNX1 mRNA:miR-215 RISCTBarR-HSA-8935785 (Reactome)
RUNX1 mRNA:miR-27a

Nonendonucleolytic

RISC
ArrowR-HSA-8937134 (Reactome)
RUNX1 mRNA:miR-27a

Nonendonucleolytic

RISC
TBarR-HSA-8935785 (Reactome)
RUNX1 mRNA:miR-302b RISCArrowR-HSA-8935864 (Reactome)
RUNX1 mRNA:miR-302b RISCTBarR-HSA-8935785 (Reactome)
RUNX1 mRNA:miR-378

Nonendonucleolytic

RISC
ArrowR-HSA-8935766 (Reactome)
RUNX1 mRNA:miR-378

Nonendonucleolytic

RISC
TBarR-HSA-8935785 (Reactome)
RUNX1 mRNA:miR-675 RISCArrowR-HSA-8936058 (Reactome)
RUNX1 mRNA:miR-675 RISCTBarR-HSA-8935785 (Reactome)
RUNX1 mRNAR-HSA-8935766 (Reactome)
RUNX1 mRNAR-HSA-8935785 (Reactome)
RUNX1 mRNAR-HSA-8935864 (Reactome)
RUNX1 mRNAR-HSA-8935930 (Reactome)
RUNX1 mRNAR-HSA-8936058 (Reactome)
RUNX1 mRNAR-HSA-8937134 (Reactome)
RUNX1 mRNAR-HSA-8938440 (Reactome)
RUNX1 mRNAR-HSA-8938487 (Reactome)
RUNX1 mRNAR-HSA-8938507 (Reactome)
RUNX1 mRNAR-HSA-8939129 (Reactome)
RUNX1,RUNX1:CBFB:CDK6ArrowR-HSA-8938853 (Reactome)
RUNX1,RUNX1:CBFBR-HSA-8938853 (Reactome)
RUNX1:CBFBArrowR-HSA-8865320 (Reactome)
RUNX1:CCND3,(CCND1,CCND2)ArrowR-HSA-8938867 (Reactome)
RUNX1:CCND3,(CCND1,CCND2)TBarR-HSA-8865320 (Reactome)
RUNX1:PMLArrowR-HSA-8938887 (Reactome)
RUNX1ArrowR-HSA-8935785 (Reactome)
RUNX1ArrowR-HSA-8937767 (Reactome)
RUNX1R-HSA-8865320 (Reactome)
RUNX1R-HSA-8937682 (Reactome)
RUNX1R-HSA-8938867 (Reactome)
RUNX1R-HSA-8938887 (Reactome)
TBarR-HSA-8935785 (Reactome)
lncRNA H19R-HSA-8936068 (Reactome)
miR-106a

Nonendonucleolytic

RISC
R-HSA-8938507 (Reactome)
miR-17

Nonendonucleolytic

RISC
R-HSA-8938440 (Reactome)
miR-18a RISCR-HSA-8935930 (Reactome)
miR-20a

Nonendonucleolytic

RISC
R-HSA-8938487 (Reactome)
miR-215 RISCR-HSA-8939129 (Reactome)
miR-27a

Nonendonucleolytic

RISC
R-HSA-8937134 (Reactome)
miR-302b RISCR-HSA-8935864 (Reactome)
miR-378

Nonendonucleolytic

RISC
R-HSA-8935766 (Reactome)
miR-675 RISCArrowR-HSA-8936068 (Reactome)
miR-675 RISCR-HSA-8936058 (Reactome)
p-7Y-RUNX1:PTPN11ArrowR-HSA-8937744 (Reactome)
p-7Y-RUNX1:PTPN11R-HSA-8937767 (Reactome)
p-7Y-RUNX1:PTPN11mim-catalysisR-HSA-8937767 (Reactome)
p-7Y-RUNX1ArrowR-HSA-8937728 (Reactome)
p-7Y-RUNX1R-HSA-8937744 (Reactome)
p-Y419-SRC:RUNX1ArrowR-HSA-8937682 (Reactome)
p-Y419-SRC:RUNX1R-HSA-8937728 (Reactome)
p-Y419-SRC:RUNX1mim-catalysisR-HSA-8937728 (Reactome)
p-Y419-SRCArrowR-HSA-8937728 (Reactome)
p-Y419-SRCR-HSA-8937682 (Reactome)
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