Biology:RUNX3

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Runt-related transcription factor 3 is a protein that in humans is encoded by the RUNX3 gene.[1]

Function

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,[2] 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.[3]

In melanocytic cells RUNX3 gene expression may be regulated by MITF.[4]

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)[5] and to subsequent transient induction of CDKN1A and ARF.[6] CDKN1A (also known as CIP1 or p21) inhibits the cell cycle, and ARF inhibits MDM2, increasing the stability of the cancer-suppressing gene p53.[6]

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.[6]

Knockout mouse

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.[7]

The RUNX3 controversy and resolution

In 2011 doubt was cast over the tumor suppressor function of Runx3 originated from the earlier publication by Li and co-workers.[8] 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.[9]

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.[10] 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.

Interactions

RUNX3 has been shown to interact with TLE1.[11]

See also

References

  1. ↑ "AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization". Genomics 23 (2): 425–32. Sep 1994. doi:10.1006/geno.1994.1519. PMID 7835892. 
  2. ↑ "Site-directed mutagenesis supports a three-dimensional model of the runt domain". Journal of Molecular Biology 277 (3): 509–12. Apr 1998. doi:10.1006/jmbi.1998.1633. PMID 9533875. 
  3. ↑ "Entrez Gene: RUNX3 runt-related transcription factor 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=864. 
  4. ↑ "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research 21 (6): 665–76. Dec 2008. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 
  5. ↑ Lee, You-Soub; Lee, Jung-Won; Jang, Ju-Won; Chi, Xin-Zi; Kim, Jang-Hyun; Li, Ying-Hui; Kim, Min-Kyu; Kim, Da-Mi et al. (2013-11-11). "Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma". Cancer Cell 24 (5): 603–616. doi:10.1016/j.ccr.2013.10.003. ISSN 1878-3686. PMID 24229708. 
  6. ↑ 6.0 6.1 6.2 Lee, Jung-Won; Kim, Da-Mi; Jang, Ju-Won; Park, Tae-Geun; Song, Soo-Hyun; Lee, You-Soub; Chi, Xin-Zi; Park, Il Yeong et al. (2019-04-23). "RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point" (in en). Nature Communications 10 (1): 1897. doi:10.1038/s41467-019-09810-w. ISSN 2041-1723. PMID 31015486. Bibcode: 2019NatCo..10.1897L. 
  7. ↑ "Causal relationship between the loss of RUNX3 expression and gastric cancer". Cell 109 (1): 113–24. Apr 2002. doi:10.1016/S0092-8674(02)00690-6. PMID 11955451. 
  8. ↑ "Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function". EMBO Mol Med 3 (10): 593–604. Oct 2011. doi:10.1002/emmm.201100168. PMID 21786422. 
  9. ↑ Maiväli, Ülo (2015). Interpreting Biomedical Science. Academic Press. pp. 44–45. ISBN 9780124186897. http://store.elsevier.com/Interpreting-Biomedical-Science/%C3%9Clo-Maiv%C3%A4li/isbn-9780124186897/. 
  10. ↑ Ito, K.; Inoue, K.-i; Bae, S.-C.; Ito, Y. (2009-03-12). "Runx3 expression in gastrointestinal tract epithelium: resolving the controversy". Oncogene 28 (10): 1379–1384. doi:10.1038/onc.2008.496. ISSN 1476-5594. PMID 19169278. https://pubmed.ncbi.nlm.nih.gov/19169278. 
  11. ↑ "Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors". Proceedings of the National Academy of Sciences of the United States of America 95 (20): 11590–5. Sep 1998. doi:10.1073/pnas.95.20.11590. PMID 9751710. Bibcode: 1998PNAS...9511590L. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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