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Gene Review

Runx2  -  runt related transcription factor 2

Mus musculus

Synonyms: AML3, Acute myeloid leukemia 3 protein, Aml3, CBF-alpha-1, Cbf, ...
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Disease relevance of Runx2


High impact information on Runx2


Biological context of Runx2

  • Moreover, Runx2 directly bound to the promoter region of the Ihh gene and strongly induced expression of the reporter gene driven by the Ihh promoter [10].
  • Further, the length of the limbs was reduced depending on the dosages of Runx2 and Runx3, due to reduced and disorganized chondrocyte proliferation and reduced cell size in the diaphyses [10].
  • Our results indicate that Runx2 is a major target gene shared by TGF-beta and BMP signaling pathways and that the coordinated action of Runx2 and BMP-activated Smads leads to the induction of osteoblast-specific gene expression in C2C12 cells [11].
  • This stimulation required Runx2 and its DNA binding site in the osteocalcin promoter [12].
  • Thus, this study demonstrates that the activation of PPARgamma inhibits osteocalcin expression both by suppressing the expression of Runx2 and by interfering with the transactivation ability of Runx2 [13].

Anatomical context of Runx2


Associations of Runx2 with chemical compounds

  • Treatment of MC3T3-E1 osteoblasts and ROS 17/2.8 cells stably transfected with PPARgamma2 with the PPARgamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibited the mRNA expression of osteocalcin and Runx2, the latter of which is a key transcription factor in osteoblast differentiation [13].
  • Deletion analysis showed that the leucine zipper domain of ATF4 is critical for Runx2 activation [17].
  • In contrast, pull-down assays using purified glutathione S-transferase fusion proteins were unable to demonstrate a direct physical interaction between ATF4 and Runx2 [17].
  • Consistent with these cell type-specific effects, expression of the adipocyte-specific gene marker FABP4/aP2 was increased, whereas the expression of osteoblast-specific gene markers, Runx2, Dlx5, osteocalcin, and collagen were not affected by netoglitazone [18].
  • Forced expression of Runx2 enhanced osteoblastic differentiation of C3H10T1/2 and MC3T3-E1 cells and enhanced chondrogenic differentiation of ATDC5 cells, whereas these effects were blocked by treatment with IGF-I antibody or LY294002 or adenoviral introduction of dominant-negative (dn)-Akt [19].

Physical interactions of Runx2

  • E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation [20].
  • Functional relevance was demonstrated through mutations in the Ets-1 and Runx2 consensus binding sites resulting in >60% decrease in OPN transcription [2].
  • Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice [21].
  • Actually, Stat1 interacts with Runx2 in its latent form in the cytoplasm, thereby inhibiting the nuclear localization of Runx2, an essential transcription factor for osteoblast differentiation [22].
  • Treatment with LY294002 or introduction of dn-Akt severely diminished DNA binding of Runx2 and Runx2-dependent transcription, whereas forced expression of myrAkt enhanced them [19].
  • Notwithstanding its growth-suppressive potential, our results surprisingly indicate that Runx2 may sensitize cAMP-related G protein-coupled receptor signaling by activating Gpr30 and repressing Rgs2 gene expression in osteoblasts to increase responsiveness to mitogenic signals [23].

Co-localisations of Runx2


Regulatory relationships of Runx2


Other interactions of Runx2

  • Both a Runx2 site (-136/-130) and the vitamin D response element (-757/-743) in the OPN promoter are needed for cooperative activation [25].
  • To better understand Msx2 regulation of the OCFRE, we have studied functional interactions between MINT and Runx2, a master regulator of osteoblast differentiation [26].
  • Recently we have found that Smurf1 mediates the protein degradation of the osteoblast-specific transcription factor Runx2/Cbfa1 [29].
  • Overall, the expression of Runx1 remained significantly higher than Runx2 mRNA levels during early limb bud cell maturation [3].
  • We have recently shown that over-expression of the full-length, most highly expressed Runx2 isoform in the thymus perturbs T-cell development, leads to development of spontaneous lymphomas at low frequency and is strongly synergistic with Myc [30].

Analytical, diagnostic and therapeutic context of Runx2


  1. Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection. Vaillant, F., Blyth, K., Andrew, L., Neil, J.C., Cameron, E.R. J. Immunol. (2002) [Pubmed]
  2. Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. Wai, P.Y., Mi, Z., Gao, C., Guo, H., Marroquin, C., Kuo, P.C. J. Biol. Chem. (2006) [Pubmed]
  3. Runx1/AML1/Cbfa2 mediates onset of mesenchymal cell differentiation toward chondrogenesis. Wang, Y., Belflower, R.M., Dong, Y.F., Schwarz, E.M., O'Keefe, R.J., Drissi, H. J. Bone Miner. Res. (2005) [Pubmed]
  4. The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts. Galindo, M., Pratap, J., Young, D.W., Hovhannisyan, H., Im, H.J., Choi, J.Y., Lian, J.B., Stein, J.L., Stein, G.S., van Wijnen, A.J. J. Biol. Chem. (2005) [Pubmed]
  5. Transient changes in oxygen tension inhibit osteogenic differentiation and Runx2 expression in osteoblasts. Salim, A., Nacamuli, R.P., Morgan, E.F., Giaccia, A.J., Longaker, M.T. J. Biol. Chem. (2004) [Pubmed]
  6. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Vega, R.B., Matsuda, K., Oh, J., Barbosa, A.C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J.M., Richardson, J.A., Karsenty, G., Olson, E.N. Cell (2004) [Pubmed]
  7. TSH is a negative regulator of skeletal remodeling. Abe, E., Marians, R.C., Yu, W., Wu, X.B., Ando, T., Li, Y., Iqbal, J., Eldeiry, L., Rajendren, G., Blair, H.C., Davies, T.F., Zaidi, M. Cell (2003) [Pubmed]
  8. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J.M., Behringer, R.R., de Crombrugghe, B. Cell (2002) [Pubmed]
  9. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., Sato, M., Okamoto, R., Kitamura, Y., Yoshiki, S., Kishimoto, T. Cell (1997) [Pubmed]
  10. 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]
  11. Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Lee, K.S., Kim, H.J., Li, Q.L., Chi, X.Z., Ueta, C., Komori, T., Wozney, J.M., Kim, E.G., Choi, J.Y., Ryoo, H.M., Bae, S.C. Mol. Cell. Biol. (2000) [Pubmed]
  12. Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. Xiao, G., Jiang, D., Gopalakrishnan, R., Franceschi, R.T. J. Biol. Chem. (2002) [Pubmed]
  13. Activation of peroxisome proliferator-activated receptor-gamma inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts. Jeon, M.J., Kim, J.A., Kwon, S.H., Kim, S.W., Park, K.S., Park, S.W., Kim, S.Y., Shin, C.S. J. Biol. Chem. (2003) [Pubmed]
  14. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Akiyama, H., Chaboissier, M.C., Martin, J.F., Schedl, A., de Crombrugghe, B. Genes Dev. (2002) [Pubmed]
  15. The osteoblast transcription factor Runx2 is expressed in mammary epithelial cells and mediates osteopontin expression. Inman, C.K., Shore, P. J. Biol. Chem. (2003) [Pubmed]
  16. Differential expression patterns of Runx2 isoforms in cranial suture morphogenesis. Park, M.H., Shin, H.I., Choi, J.Y., Nam, S.H., Kim, Y.J., Kim, H.J., Ryoo, H.M. J. Bone Miner. Res. (2001) [Pubmed]
  17. Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. Xiao, G., Jiang, D., Ge, C., Zhao, Z., Lai, Y., Boules, H., Phimphilai, M., Yang, X., Karsenty, G., Franceschi, R.T. J. Biol. Chem. (2005) [Pubmed]
  18. Netoglitazone is a PPAR-gamma ligand with selective effects on bone and fat. Lazarenko, O.P., Rzonca, S.O., Suva, L.J., Lecka-Czernik, B. Bone (2006) [Pubmed]
  19. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. Fujita, T., Azuma, Y., Fukuyama, R., Hattori, Y., Yoshida, C., Koida, M., Ogita, K., Komori, T. J. Cell Biol. (2004) [Pubmed]
  20. E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation. Zhao, M., Qiao, M., Oyajobi, B.O., Mundy, G.R., Chen, D. J. Biol. Chem. (2003) [Pubmed]
  21. Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice. Wang, W., Wang, Y.G., Reginato, A.M., Glotzer, D.J., Fukai, N., Plotkina, S., Karsenty, G., Olsen, B.R. Dev. Biol. (2004) [Pubmed]
  22. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Kim, S., Koga, T., Isobe, M., Kern, B.E., Yokochi, T., Chin, Y.E., Karsenty, G., Taniguchi, T., Takayanagi, H. Genes Dev. (2003) [Pubmed]
  23. Runx2 regulates G protein-coupled signaling pathways to control growth of osteoblast progenitors. Teplyuk, N.M., Galindo, M., Teplyuk, V.I., Pratap, J., Young, D.W., Lapointe, D., Javed, A., Stein, J.L., Lian, J.B., Stein, G.S., van Wijnen, A.J. J. Biol. Chem. (2008) [Pubmed]
  24. Fibroblast growth factor signaling regulates Dach1 expression during skeletal development. Horner, A., Shum, L., Ayres, J.A., Nonaka, K., Nuckolls, G.H. Dev. Dyn. (2002) [Pubmed]
  25. The vitamin D receptor, Runx2, and the Notch signaling pathway cooperate in the transcriptional regulation of osteopontin. Shen, Q., Christakos, S. J. Biol. Chem. (2005) [Pubmed]
  26. MINT, the Msx2 interacting nuclear matrix target, enhances Runx2-dependent activation of the osteocalcin fibroblast growth factor response element. Sierra, O.L., Cheng, S.L., Loewy, A.P., Charlton-Kachigian, N., Towler, D.A. J. Biol. Chem. (2004) [Pubmed]
  27. 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]
  28. Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development. Choi, K.Y., Kim, H.J., Lee, M.H., Kwon, T.G., Nah, H.D., Furuichi, T., Komori, T., Nam, S.H., Kim, Y.J., Kim, H.J., Ryoo, H.M. Dev. Dyn. (2005) [Pubmed]
  29. Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. Zhao, M., Qiao, M., Harris, S.E., Oyajobi, B.O., Mundy, G.R., Chen, D. J. Biol. Chem. (2004) [Pubmed]
  30. Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging. Blyth, K., Terry, A., Mackay, N., Vaillant, F., Bell, M., Cameron, E.R., Neil, J.C., Stewart, M. Oncogene (2001) [Pubmed]
  31. Different roles of Runx2 during early neural crest-derived bone and tooth development. James, M.J., Järvinen, E., Wang, X.P., Thesleff, I. J. Bone Miner. Res. (2006) [Pubmed]
  32. Cbf beta regulates Runx2 function isoform-dependently in postnatal bone development. Kanatani, N., Fujita, T., Fukuyama, R., Liu, W., Yoshida, C.A., Moriishi, T., Yamana, K., Miyazaki, T., Toyosawa, S., Komori, T. Dev. Biol. (2006) [Pubmed]
  33. Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. Hinoi, E., Fujimori, S., Wang, L., Hojo, H., Uno, K., Yoneda, Y. J. Biol. Chem. (2006) [Pubmed]
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