Regulation of RUNX3 expression and activity

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R-HSA-8941858
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Homo sapiens
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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 (Whittle et al. 2015). 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 (Lee et al. 2009).
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 (Lai et al. 2010, Paudel et al. 2016).
Similar to RUNX1 and RUNX2, RUNX3 forms a transcriptionally active heterodimer with CBFB (CBF-beta) (Kim et al. 2013). 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 (Goh et al. 2010). Subcellular localization of RUNX3 may be affected by PIM1-mediated phosphorylation (Kim et al. 2008).
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) (Puig-Kroger et al. 2010).
E3 ubiquitin ligases MDM2 (Chi et al. 2009), SMURF1 and SMURF2 (Jin et al. 2004) are implicated in RUNX3 polyubiquitination and degradation.

Literature References
PubMed ID Title Journal Year
19808967 Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination

Chi, XZ, Kim, J, Lee, YH, Lee, JW, Lee, KS, Wee, H, Kim, WJ, Park, WY, Oh, BC, Stein, GS, Ito, Y, van Wijnen, AJ, Bae, SC

Cancer Res. 2009
18767071 Pim-1 kinase phosphorylates and stabilizes RUNX3 and alters its subcellular localization

Kim, HR, Oh, BC, Choi, JK, Bae, SC

J. Cell. Biochem. 2008
18850007 Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells

Lee, SH, Kim, J, Kim, WH, Lee, YM

Oncogene 2009
26004068 RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma

Whittle, MC, Izeradjene, K, Rani, PG, Feng, L, Carlson, MA, DelGiorno, KE, Wood, LD, Goggins, M, Hruban, RH, Chang, AE, Calses, P, Thorsen, SM, Hingorani, SR

Cell 2015
15138260 Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation

Jin, YH, Jeon, EJ, Li, QL, Lee, YH, Choi, JK, Kim, WJ, Lee, KY, Bae, SC

J. Biol. Chem. 2004
23333304 CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression

Kim, DY, Kwon, E, Hartley, PD, Crosby, DC, Mann, S, Krogan, NJ, Gross, JD

Mol. Cell 2013
20100835 Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm

Goh, YM, Cinghu, S, Hong, ET, Lee, YS, Kim, JH, Jang, JW, Li, YH, Chi, XZ, Lee, KS, Wee, H, Ito, Y, Oh, BC, Bae, SC

J. Biol. Chem. 2010
27048832 MicroRNA-130b functions as a tumor suppressor by regulating RUNX3 in epithelial ovarian cancer

Paudel, D, Zhou, W, Ouyang, Y, Dong, S, Huang, Q, Giri, R, Wang, J, Tong, X

Gene 2016
15156175 Structure and regulated expression of mammalian RUNX genes

Levanon, D, Groner, Y

Oncogene 2004
20176475 MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer

Lai, KW, Koh, KX, Loh, M, Tada, K, Subramaniam, MM, Lim, XY, Vaithilingam, A, Salto-Tellez, M, Iacopetta, B, Ito, Y, Soong, R

Eur. J. Cancer 2010
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