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Gene Review

Runx3  -  runt related transcription factor 3

Mus musculus

Synonyms: AML2, Acute myeloid leukemia 2 protein, Aml2, CBF-alpha-3, Cbfa3, ...
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Disease relevance of Runx3

  • Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons [1].
  • Since Runxl and Runx3 are involved in the development of some cancers including acute leukemia and gastric cancer, it will be of interest to examine in detail whether TGF-beta-specific R-Smads and Runx proteins coordinately regulate growth and differentiation of hematopoietic cells and gastric epithelial cells [2].
  • Overexpression of Runx3 in mice increased germ-line alpha (GLalpha) transcription, and transcription was further augmented when B lymphoma and LPS-activated murine spleen cells were co-transfected with Smad3/4 [3].
  • Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells [4].
  • Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion [5].

High impact information on Runx3

  • Runx3-deficient cytotoxic T cells, but not helper cells, have defective responses to antigen, suggesting that Runx proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes [6].
  • We found that chondrocyte differentiation was inhibited depending on the dosages of Runx2 and Runx3, and Runx2(-/-)3(-/-) mice showed a complete absence of chondrocyte maturation [7].
  • With CD27 to distinguish pre- and postselection DN3 cells, a detailed gene expression analysis defined regulatory changes associated with checkpoint arrest, with beta selection, and with gammadelta selection. gammadelta selection induces higher CD5, Egr, and Runx3 expression as compared to beta selection, but it triggers less proliferation [8].
  • Among Runx family members, Runx3 expression was initiated in DP thymocytes receiving a positive selection signal and increased in concert with differentiation to the CD8SP stage [9].
  • TOX-mediated positive selection is associated with up-regulation of Runx3, implicating CD4 silencing in the process [10].

Chemical compound and disease context of Runx3


Biological context of Runx3

  • Comparison with the syntenic region of human chromosome 1 shows that the next gene is over 250 kb 5' to Runx3, suggesting that Runx3 may be the primary target of retroviral insertions at Dsi1 [12].
  • Here, we describe the expression pattern of Runx3 during mouse embryogenesis compared to the expression pattern of Runx1 [13].
  • However, Runx3 mutant mice did not show obvious tooth phenotype or deviations of Runx1 and Runx2 expression patterns in the tooth [14].
  • In early tooth morphogenesis Runx3 was coexpressed with Runx2 in a thin layer of mesenchymal cells underlying dental epithelium [14].
  • The human RUNX3/AML2 gene belongs to the 'runt domain' family of transcription factors that act as gene expression regulators in major developmental pathways [13].

Anatomical context of Runx3


Associations of Runx3 with chemical compounds

  • In this study we have investigated the role of Runx3 during thymocyte development and CD4 silencing and have identified integrin alpha(E)/CD103 on CD8 SP T cells as a new potential target gene of Runx3 [17].
  • Although two of the sites we tested in the promoter of the fourth line were not methylated, in all four cases the silencing of Runx3 could be reversed by treatment of the cells with 5'-azacytidine and trichostatin A [11].

Physical interactions of Runx3


Regulatory relationships of Runx3

  • Runx1 was expressed in several cartilage primordia earlier than Runx3, and Runx2 was intense in all mesenchymal condensations of bones and teeth [14].
  • Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation [5].
  • These results suggest that Runx3 positively regulates the expression of TrkC and TrkA in DRG neurons [19].

Other interactions of Runx3

  • Runx1 and Runx3 are known to be involved in leukemogenesis and gastric carcinogenesis, respectively [20].
  • Here we report that Runx3-deficient (Runx3(-/-)) mice displayed severe motor uncoordination and that few DRG neurons synthesized the proprioceptive neuronal marker parvalbumin [1].
  • p300 cooperates with Smad3/4 and Runx3 in TGFbeta1-induced IgA isotype expression [3].
  • Here we show that Runx3-/- mice display severe limb ataxia and abnormal posture and that most of them die shortly after birth [21].
  • In Runx3-/- mouse gastric epithelium, Bim was down-regulated, and apoptosis was reduced to the same extent as that in Bim-/- gastric epithelium [22].

Analytical, diagnostic and therapeutic context of Runx3

  • To analyze the role of runx genes in skeletal development, we performed in situ hybridization with Runx2- and Runx3-specific probes [23].
  • E10.5 and E14.5-E16.5 embryos were analyzed using both immunohistochemistry and beta-galactosidase activity of targeted Runx3 and Runx1 loci [13].


  1. Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Inoue, K., Ozaki, S., Shiga, T., Ito, K., Masuda, T., Okado, N., Iseda, T., Kawaguchi, S., Ogawa, M., Bae, S.C., Yamashita, N., Itohara, S., Kudo, N., Ito, Y. Nat. Neurosci. (2002) [Pubmed]
  2. Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins. Miyazono, K., Maeda, S., Imamura, T. Oncogene (2004) [Pubmed]
  3. p300 cooperates with Smad3/4 and Runx3 in TGFbeta1-induced IgA isotype expression. Park, S.R., Lee, E.K., Kim, B.C., Kim, P.H. Eur. J. Immunol. (2003) [Pubmed]
  4. Causal relationship between the loss of RUNX3 expression and gastric cancer. Li, Q.L., Ito, K., Sakakura, C., Fukamachi, H., Inoue, K., Chi, X.Z., Lee, K.Y., Nomura, S., Lee, C.W., Han, S.B., Kim, H.M., Kim, W.J., 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, S.C., Ito, Y. Cell (2002) [Pubmed]
  5. Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation. Fainaru, O., Woolf, E., Lotem, J., Yarmus, M., Brenner, O., Goldenberg, D., Negreanu, V., Bernstein, Y., Levanon, D., Jung, S., Groner, Y. EMBO J. (2004) [Pubmed]
  6. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Taniuchi, I., Osato, M., Egawa, T., Sunshine, M.J., Bae, S.C., Komori, T., Ito, Y., Littman, D.R. Cell (2002) [Pubmed]
  7. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Yoshida, C.A., Yamamoto, H., Fujita, T., Furuichi, T., Ito, K., Inoue, K., Yamana, K., Zanma, A., Takada, K., Ito, Y., Komori, T. Genes Dev. (2004) [Pubmed]
  8. Developmental and molecular characterization of emerging beta- and gammadelta-selected pre-T cells in the adult mouse thymus. Taghon, T., Yui, M.A., Pant, R., Diamond, R.A., Rothenberg, E.V. Immunity (2006) [Pubmed]
  9. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Sato, T., Ohno, S., Hayashi, T., Sato, C., Kohu, K., Satake, M., Habu, S. Immunity (2005) [Pubmed]
  10. TOX provides a link between calcineurin activation and CD8 lineage commitment. Aliahmad, P., O'Flaherty, E., Han, P., Goularte, O.D., Wilkinson, B., Satake, M., Molkentin, J.D., Kaye, J. J. Exp. Med. (2004) [Pubmed]
  11. Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor. Guo, W.H., Weng, L.Q., Ito, K., Chen, L.F., Nakanishi, H., Tatematsu, M., Ito, Y. Oncogene (2002) [Pubmed]
  12. The common retroviral insertion locus Dsi1 maps 30 kilobases upstream of the P1 promoter of the murine Runx3/Cbfa3/Aml2 gene. Stewart, M., MacKay, N., Cameron, E.R., Neil, J.C. J. Virol. (2002) [Pubmed]
  13. Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis. Levanon, D., Brenner, O., Negreanu, V., Bettoun, D., Woolf, E., Eilam, R., Lotem, J., Gat, U., Otto, F., Speck, N., Groner, Y. Mech. Dev. (2001) [Pubmed]
  14. Expression of Runx1, -2 and -3 during tooth, palate and craniofacial bone development. Yamashiro, T., Aberg, T., Levanon, D., Groner, Y., Thesleff, I. Gene Expr. Patterns (2002) [Pubmed]
  15. Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Aberg, T., Wang, X.P., Kim, J.H., Yamashiro, T., Bei, M., Rice, R., Ryoo, H.M., Thesleff, I. Dev. Biol. (2004) [Pubmed]
  16. Runx3 expression during mouse tongue and palate development. Yamamoto, H., Ito, K., Kawai, M., Murakami, Y., Bessho, K., Ito, Y. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. (2006) [Pubmed]
  17. Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells. Grueter, B., Petter, M., Egawa, T., Laule-Kilian, K., Aldrian, C.J., Wuerch, A., Ludwig, Y., Fukuyama, H., Wardemann, H., Waldschuetz, R., Möröy, T., Taniuchi, I., Steimle, V., Littman, D.R., Ehlers, M. J. Immunol. (2005) [Pubmed]
  18. Pim-1 kinase phosphorylates RUNX family transcription factors and enhances their activity. Aho, T.L., Sandholm, J., Peltola, K.J., Ito, Y., Koskinen, P.J. BMC Cell Biol. (2006) [Pubmed]
  19. Dynamic regulation of the expression of neurotrophin receptors by Runx3. Nakamura, S., Senzaki, K., Yoshikawa, M., Nishimura, M., Inoue, K., Ito, Y., Ozaki, S., Shiga, T. Development (2008) [Pubmed]
  20. Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein. Lee, K.S., Hong, S.H., Bae, S.C. Oncogene (2002) [Pubmed]
  21. Runx3 is essential for the target-specific axon pathfinding of trkc-expressing dorsal root ganglion neurons. Inoue, K., Ozaki, S., Ito, K., Iseda, T., Kawaguchi, S., Ogawa, M., Bae, S.C., Yamashita, N., Itohara, S., Kudo, N., Ito, Y. Blood Cells Mol. Dis. (2003) [Pubmed]
  22. The RUNX3 tumor suppressor upregulates Bim in gastric epithelial cells undergoing transforming growth factor beta-induced apoptosis. Yano, T., Ito, K., Fukamachi, H., Chi, X.Z., Wee, H.J., Inoue, K., Ida, H., Bouillet, P., Strasser, A., Bae, S.C., Ito, Y. Mol. Cell. Biol. (2006) [Pubmed]
  23. Role of Runx genes in chondrocyte differentiation. Stricker, S., Fundele, R., Vortkamp, A., Mundlos, S. Dev. Biol. (2002) [Pubmed]
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