Pathway
Regulation of RUNX3 expression and activity
RUNX3, like other RUNX family members, is transcribed from two promoters - the proximal P2 promoter and the distal P1 promoter. The P2 promoter is positioned within a large CpG island that is frequently methylated in solid tumors, resulting in epigenetic inactivation of the RUNX3 gene (reviewed by Levanon and Groner 2004). RUNX3 transcription is affected by SMAD4 levels. RUNX3 may directly upregulate its own transcription through a positive feedback loop. Under hypoxic conditions, RUNX3 transcription is downregulated. Hypoxic silencing of RUNX3 involves hypoxia-induced upregulation of the histone methyltransferase G9a and histone deacetylase HDAC1, which leads to increased dimethylation of histone H3 at lysine residue K9 (K10 when taking into account the initiator methionine) and reduced acetylation of histone H3 at the RUNX3 promoter.
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RUNX3 protein levels are inversely related to the levels of microRNA miR-130b. Based on in silico analysis, RUNX3 is predicted to be the target of miR-130b, but binding assays and 3'UTR reporter assays have not been done to confirm this.
Similar to RUNX1 and RUNX2, RUNX3 forms a transcriptionally active heterodimer with CBFB (CBF-beta). RUNX3 activity can be regulated by changes in RUNX3 localization. SRC protein tyrosine kinase phosphorylates RUNX3 on multiple tyrosine residues, inhibiting its translocation from the cytosol to the nucleus and thus inhibiting RUNX3-mediated transcription. Subcellular localization of RUNX3 may be affected by PIM1-mediated phosphorylation.
The P1 and P2 promoters regulate RUNX3 transcription in a cell-type/differentiation dependent manner, giving rise to the p44 and p46 isoforms of RUNX3, respectively. Several splicing isoforms have also been reported. One example is the generation of a 33 kDa protein isoform (p33) by alternative splicing. The RUNX3 p33 isoform lacks the Runt domain and is unable to transactivate the regulatory regions of integrin genes. The p33 isoform is induced during maturation of monocyte-derived dendritic cells (MDDC), leading to reduced expression of genes involved in inflammatory responses, such as IL8 (interleukin-8).
E3 ubiquitin ligases MDM2, SMURF1 and SMURF2 are implicated in RUNX3 polyubiquitination and degradation.
What the reference databases state
Statements
45 statements
45 statements · 1 reference database · Subject: Regulation of RUNX3 expression and activity · Sources: Reactome
- ADRM1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- CBFB participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- CDKN2A participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- EP300 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- MDM2 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA2 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA3 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA4 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA5 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA6 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMA7 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
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- PSMB1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMB2 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMB3 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMB4 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMB5 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMB6 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMB7 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMC1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMC2 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMC3 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMC4 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMC5 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMC6 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD11 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD12 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD13 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD14 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD2 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD3 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD6 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD7 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- PSMD8 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- RPS27A participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- RUNX3 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- SEM1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- SMURF1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- SMURF2 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- SRC participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- TGFB1 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- UBA52 participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- UBB participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only
- UBC participates in Regulation of RUNX3 expression and activityProteinReactome R-HSA-8941858Inferred only