Wikipedia

RUNX3

Runt-related transcription factor 3 is a protein that in humans is encoded by the RUNX3 gene.[5]

RUNX3
Identifiers
AliasesRUNX3, AML2, CBFA3, PEBP2aC, runt related transcription factor 3, RUNX family transcription factor 3
External IDsOMIM: 600210; MGI: 102672; HomoloGene: 37914; GeneCards: RUNX3; OMA:RUNX3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

864

12399

Ensembl

ENSG00000020633

ENSMUSG00000070691

UniProt

Q13761

Q3U1Q3

RefSeq (mRNA)

NM_001031680
NM_004350
NM_001320672

NM_019732
NM_001369050

RefSeq (protein)

NP_001026850
NP_001307601
NP_004341

NP_062706
NP_001355979

Location (UCSC)Chr 1: 24.9 – 24.97 MbChr 4: 134.85 – 134.91 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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]

Knockout mouse

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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]

The RUNX3 controversy and resolution

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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.

Interactions

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RUNX3 has been shown to interact with TLE1.[15]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000020633 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000070691 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Levanon D, Negreanu V, Bernstein Y, Bar-Am I, Avivi L, Groner Y (September 1994). "AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization". Genomics. 23 (2): 425–432. doi:10.1006/geno.1994.1519. PMID 7835892.
  6. ^ Levanon D, Eisenstein M, Groner Y (April 1998). "Site-directed mutagenesis supports a three-dimensional model of the runt domain". Journal of Molecular Biology. 277 (3): 509–512. doi:10.1006/jmbi.1998.1633. PMID 9533875. S2CID 13139512.
  7. ^ "Entrez Gene: RUNX3 runt-related transcription factor 3".
  8. ^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, et al. (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–676. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  9. ^ Lee YS, Lee JW, Jang JW, Chi XZ, Kim JH, Li YH, et al. (November 2013). "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. PMID 24229708.
  10. ^ a b c Lee JW, Kim DM, Jang JW, Park TG, Song SH, Lee YS, et al. (April 2019). "RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point". Nature Communications. 10 (1): 1897. Bibcode:2019NatCo..10.1897L. doi:10.1038/s41467-019-09810-w. PMC 6479060. PMID 31015486.
  11. ^ Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, et al. (April 2002). "Causal relationship between the loss of RUNX3 expression and gastric cancer". Cell. 109 (1): 113–124. doi:10.1016/S0092-8674(02)00690-6. PMID 11955451. S2CID 11362226.
  12. ^ Levanon D, Bernstein Y, Negreanu V, Bone KR, Pozner A, Eilam R, et al. (October 2011). "Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function". EMBO Molecular Medicine. 3 (10): 593–604. doi:10.1002/emmm.201100168. PMC 3258485. PMID 21786422.
  13. ^ Maiväli Ü (2015). Interpreting Biomedical Science. Academic Press. pp. 44–45. ISBN 9780124186897.
  14. ^ Ito K, Inoue KI, Bae SC, Ito Y (March 2009). "Runx3 expression in gastrointestinal tract epithelium: resolving the controversy". Oncogene. 28 (10): 1379–1384. doi:10.1038/onc.2008.496. PMID 19169278.
  15. ^ Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, et al. (September 1998). "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): 11590–11595. Bibcode:1998PNAS...9511590L. doi:10.1073/pnas.95.20.11590. PMC 21685. PMID 9751710.

Further reading

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

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