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


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]

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.[5]

The RUNX3 controversy

In 2011 serious doubt was cast over the tumor suppressor function of Runx3 originated from the earlier publication by Li and co-workers.[6] 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 novel by Ülo Maiväli.[7]


RUNX3 has been shown to interact with TLE1.[8]

See also


  1. 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. PMID 7835892.
  2. 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. PMID 9533875.
  3. "Entrez Gene: RUNX3 runt-related transcription factor 3".
  4. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (Dec 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  5. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue Ki, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y (Apr 2002). "Causal relationship between the loss of RUNX3 expression and gastric cancer". Cell. 109 (1): 113–24. doi:10.1016/S0092-8674(02)00690-6. PMID 11955451.
  6. Levanon D, Bernstein Y, Negreanu V, Bone KR, Pozner A, Eilam R, Lotem J, Brenner O, Groner Y (Oct 2011). "Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function". EMBO Mol Med. 3 (10): 593–604. doi:10.1002/emmm.201100168. PMC 3258485. PMID 21786422.
  7. Maiväli, Ülo (2015). Interpreting Biomedical Science. Academic Press. pp. 44–45. ISBN 9780124186897.
  8. Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y (Sep 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): 11590–5. doi:10.1073/pnas.95.20.11590. PMC 21685. PMID 9751710.

Further reading

  • Vogiatzi P, De Falco G, Claudio PP, Giordano A (Apr 2006). "How does the human RUNX3 gene induce apoptosis in gastric cancer? Latest data, reflections and reactions". Cancer Biology & Therapy. 5 (4): 371–4. doi:10.4161/cbt.5.4.2748. PMID 16627973.
  • Wijmenga C, Speck NA, Dracopoli NC, Hofker MH, Liu P, Collins FS (Apr 1995). "Identification of a new murine runt domain-containing gene, Cbfa3, and localization of the human homolog, CBFA3, to chromosome 1p35-pter". Genomics. 26 (3): 611–4. doi:10.1016/0888-7543(95)80185-O. PMID 7607690.
  • 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. PMID 7622058.
  • 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. PMID 8437866.
  • Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y (Sep 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): 11590–5. doi:10.1073/pnas.95.20.11590. PMC 21685. PMID 9751710.
  • Bangsow C, Rubins N, Glusman G, Bernstein Y, Negreanu V, Goldenberg D, Lotem J, Ben-Asher E, Lancet D, Levanon D, Groner Y (Nov 2001). "The RUNX3 gene--sequence, structure and regulated expression". Gene. 279 (2): 221–32. doi:10.1016/S0378-1119(01)00760-0. PMID 11733147.
  • Waki T, Tamura G, Sato M, Terashima M, Nishizuka S, Motoyama T (Apr 2003). "Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia". Cancer Science. 94 (4): 360–4. doi:10.1111/j.1349-7006.2003.tb01447.x. PMID 12824905.
  • Puig-Kröger A, Sanchez-Elsner T, Ruiz N, Andreu EJ, Prosper F, Jensen UB, Gil J, Erickson P, Drabkin H, Groner Y, Corbi AL (Nov 2003). "RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements". Blood. 102 (9): 3252–61. doi:10.1182/blood-2003-02-0618. PMID 12855590.
  • Kato N, Tamura G, Fukase M, Shibuya H, Motoyama T (Aug 2003). "Hypermethylation of the RUNX3 gene promoter in testicular yolk sac tumor of infants". The American Journal of Pathology. 163 (2): 387–91. doi:10.1016/S0002-9440(10)63668-1. PMC 1868235. PMID 12875960.
  • Yang N, Zhang L, Zhang Y, Kazazian HH (Aug 2003). "An important role for RUNX3 in human L1 transcription and retrotransposition". Nucleic Acids Research. 31 (16): 4929–40. doi:10.1093/nar/gkg663. PMC 169909. PMID 12907736.
  • 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. PMID 14715269.
  • Xiao WH, Liu WW (Feb 2004). "Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma". World Journal of Gastroenterology. 10 (3): 376–80. doi:10.3748/wjg.v10.i3.376. PMID 14760761.
  • 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. PMID 15051926.
  • Jin YH, Jeon EJ, Li QL, Lee YH, Choi JK, Kim WJ, Lee KY, Bae SC (Jul 2004). "Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation". The Journal of Biological Chemistry. 279 (28): 29409–17. doi:10.1074/jbc.M313120200. PMID 15138260.
  • 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. PMID 15273736.
  • Sakakura C, Hagiwara A, Miyagawa K, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Ito K, Yamagishi H, Yazumi S, Chiba T, Ito Y (Jan 2005). "Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer". International Journal of Cancer. 113 (2): 221–8. doi:10.1002/ijc.20551. PMID 15386419.

External links

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