This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5'-YGYGGT-3' found in a number of enhancers and promoters,[6] and can either activate or suppress transcription. It also interacts with other transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[7]
In melanocytic cells RUNX3 gene expression may be regulated by MITF.[8]
RUNX3 plays a fundamental role in defense against early tumor formation. In response to growth factors, RUNX3 is acetylated by p300 to complex with bromodomain-containing protein 2 (BRD2; a member of the BET family of transcription co-regulators)[9] and to subsequent transient induction of CDKN1A and ARF.[10] CDKN1A (also known as CIP1 or p21) inhibits the cell cycle, and ARF inhibits MDM2, increasing the stability of the cancer-suppressing gene p53.[10]
The expression of CDKN1A and ARF under wild-type cell cycles is temporary, which results from the RUNX3-BRD2 complex replacing the RUNX3-cyclinD1 complex. However, oncogenic mitogen signals such as KRASG12D cause the RUNX3-BRD2 complex to be maintained continuously, resulting in the continuous expression of p21, ARF, and p53. Therefore, RUNX3 can function as a sensor for unregulated mitogenic signals, and its inactivation can ultimately lead to cancer due to the loss of function as a sensor.[10]
Runx3 null mouse gastric mucosa exhibits hyperplasia due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to TGF-beta stimulation.[11]
In 2011 doubt was cast over the tumor suppressor function of Runx3 originated from the earlier publication by Li and co-workers.[12] On the basis of the original study by Li and co-workers (2002), the majority of later literature citing Li and co-workers (2002) assumed that RUNX3 was expressed in the normal gut epithelium and that it is therefore likely to act as a tumor suppressor in the particular epithelial cancer investigated. Most of this literature used RUNX3 promoter methylation status in various cancers as a proxy for its expression. However, quite many genes are known to be methylated in tumor cell genomes, and the majority of these genes are not expressed in the normal tissue of origin of these cancers. Others used poorly characterized (or fully invalidated) antibodies to detect the RUNX3 protein, or used RT-PCR or validated antibodies and failed to detect RUNX3 in the gut epithelium but still did not question the original finding by Li and co-workers (2002). This facts have recently been discussed in a book by Ülo Maiväli.[13]
In late 2009, a report written by Kosei Ito and his co-workers resolved the controversy by verifying that RUNX3 is indeed expressed in human and mouse gastrointestinal tract (GIT) epithelium and it functions as a tumor suppressor in gastric and colorectal tissues.[14] The authors of the paper suggested that the previous conflicting report might be caused by use of a specific antibody, known as G-poly. Ito and his team generated multiple anti-RUNX3 monoclonal antibodies recognizing the RUNX3 N-terminal region (residues 1-234). The researchers found that the antibodies react with RUNX3 in gastric epithelial cells, whereas those recognizing the C-terminal region did not. G-poly primarily recognizes the region beyond 234 and hence, is unable to detect Runx3 in this tissue.
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Levanon D, Negreanu V, Bernstein Y, Bar-Am I, Avivi L, Groner Y (Sep 1994). "AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization". Genomics. 23 (2): 425–32. doi:10.1006/geno.1994.1519. PMID7835892.
^Levanon D, Eisenstein M, Groner Y (Apr 1998). "Site-directed mutagenesis supports a three-dimensional model of the runt domain". Journal of Molecular Biology. 277 (3): 509–12. doi:10.1006/jmbi.1998.1633. PMID9533875. S2CID13139512.
Bae SC, Takahashi E, Zhang YW, Ogawa E, Shigesada K, Namba Y, Satake M, Ito Y (Jul 1995). "Cloning, mapping and expression of PEBP2 alpha C, a third gene encoding the mammalian Runt domain". Gene. 159 (2): 245–8. doi:10.1016/0378-1119(95)00060-J. PMID7622058.
Bae SC, Yamaguchi-Iwai Y, Ogawa E, Maruyama M, Inuzuka M, Kagoshima H, Shigesada K, Satake M, Ito Y (Mar 1993). "Isolation of PEBP2 alpha B cDNA representing the mouse homolog of human acute myeloid leukemia gene, AML1". Oncogene. 8 (3): 809–14. PMID8437866.
Li QL, Kim HR, Kim WJ, Choi JK, Lee YH, Kim HM, Li LS, Kim H, Chang J, Ito Y, Youl Lee K, Bae SC (Jan 2004). "Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer". Biochemical and Biophysical Research Communications. 314 (1): 223–8. doi:10.1016/j.bbrc.2003.12.079. PMID14715269.
Oshimo Y, Oue N, Mitani Y, Nakayama H, Kitadai Y, Yoshida K, Ito Y, Chayama K, Yasui W (2004). "Frequent loss of RUNX3 expression by promoter hypermethylation in gastric carcinoma". Pathobiology. 71 (3): 137–43. doi:10.1159/000076468. PMID15051926. S2CID25618007.
Ku JL, Kang SB, Shin YK, Kang HC, Hong SH, Kim IJ, Shin JH, Han IO, Park JG (Sep 2004). "Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines". Oncogene. 23 (40): 6736–42. doi:10.1038/sj.onc.1207731. PMID15273736. S2CID28548483.
1cmo: IMMUNOGLOBULIN MOTIF DNA-RECOGNITION AND HETERODIMERIZATION FOR THE PEBP2/CBF RUNT-DOMAIN
1co1: FOLD OF THE CBFA
1e50: AML1/CBF COMPLEX
1ean: THE RUNX1 RUNT DOMAIN AT 1.25A RESOLUTION: A STRUCTURAL SWITCH AND SPECIFICALLY BOUND CHLORIDE IONS MODULATE DNA BINDING
1eao: THE RUNX1 RUNT DOMAIN AT 1.25A RESOLUTION: A STRUCTURAL SWITCH AND SPECIFICALLY BOUND CHLORIDE IONS MODULATE DNA BINDING
1eaq: THE RUNX1 RUNT DOMAIN AT 1.25A RESOLUTION: A STRUCTURAL SWITCH AND SPECIFICALLY BOUND CHLORIDE IONS MODULATE DNA BINDING
1h9d: AML1/CBF-BETA/DNA COMPLEX
1hjb: CRYSTAL STRUCTURE OF RUNX-1/AML1/CBFALPHA RUNT DOMAIN AND C/EBPBETA BZIP DIMERIC BOUND TO A DNA FRAGMENT FROM THE CSF-1R PROMOTER
1hjc: CRYSTAL STRUCTURE OF RUNX-1/AML1/CBFALPHA RUNT DOMAIN BOUND TO A DNA FRAGMENT FROM THE CSF-1R PROMOTER
1io4: CRYSTAL STRUCTURE OF RUNX-1/AML1/CBFALPHA RUNT DOMAIN-CBFBETA CORE DOMAIN HETERODIMER AND C/EBPBETA BZIP HOMODIMER BOUND TO A DNA FRAGMENT FROM THE CSF-1R PROMOTER
1ljm: DNA recognition is mediated by conformational transition and by DNA bending
