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Gene Review

RUNX2  -  runt-related transcription factor 2

Homo sapiens

Synonyms: AML3, Acute myeloid leukemia 3 protein, CBF-alpha-1, CBFA1, CCD, ...
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Disease relevance of RUNX2


Psychiatry related information on RUNX2

  • CONCLUSION: Although CCD can also occur with dementia (mixed or vascular type), it is more common with multilobar lesions [8].
  • Since there are only four outputs, the amount of information transmitted to the controller is reduced (as compared to using a CCD sensor), and the reaction time of the robot is greatly decreased [9].

High impact information on RUNX2

  • Molecular analysis revealed that SATB2 directly interacts with and enhances the activity of both Runx2 and ATF4, transcription factors that regulate osteoblast differentiation [10].
  • Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation [11].
  • The Cbfb(GFP/GFP) mice exhibited a delay in endochondral and intramembranous ossification as well as in chondrocyte differentiation, similar to but less severe than delays observed in Runx2(-/-) mice [12].
  • Electrophoretic mobility shift assays and reporter assays showed that Cbfbeta was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation [11].
  • Cbfbeta interacts with Runx2 and has a critical role in bone development [12].

Chemical compound and disease context of RUNX2


Biological context of RUNX2

  • Thus, the cleidocranial bone formation, as mediated by intramembranous ossification, may require a higher level of RUNX2 than does skeletogenesis (mediated by endochondral ossification), as well as odontogenesis (involving still different complex processes) [1].
  • In contrast, two RUNX2 mutants had the Runt domain intact and remained partially competent for transactivation [1].
  • We hypothesize that the gene defect in this condition causes novel context-dependent dysregulation of multiple signaling pathways, including RUNX2, during osteoblast differentiation and craniofacial morphogenesis [18].
  • Taken together, our data show that RUNX2 is a direct regulator of Bsp in osteoblasts and that it functions in cooperation with DLX5 or a related factor to activate osteoblast-specific gene expression [19].
  • Overexpression of constitutively active MKK1 increased RUNX2 DNA binding and phosphorylation [20].

Anatomical context of RUNX2


Associations of RUNX2 with chemical compounds


Physical interactions of RUNX2


Enzymatic interactions of RUNX2


Regulatory relationships of RUNX2

  • Moreover, DBP increased gene expression of chondrogenic transcription factors SOX9 (160% of control) and RUNX2 (180%) [36].
  • Here we show that IGF-1 and its receptor regulate post-translational changes in RUNX2 to activate DNA binding in proliferating EC [20].
  • CONCLUSIONS: Both TGF-beta and BMP activate transcription of RUNX2, which is sufficient to inhibit myogenesis [37].
  • Cell lines expressing this Runx2 mutant protein inhibit the osteogenic properties of bone marrow stromal cells in coculture assays [5].
  • These findings indicate that PLZF plays important roles in early osteoblastic differentiation as an upstream regulator of CBFA1 and thereby might participate in promoting the ossification of spinal ligament cells in OPLL patients [38].
  • Human COL10A1 promoter activity was enhanced by RUNX-2 alone and more potently by RUNX-2 in combination with the coactivator core-binding factor beta in all 3 human cell lines examined [39].

Other interactions of RUNX2

  • Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2 [40].
  • RUNX1, RUNX2, and RUNX3 are highly conserved in their DNA binding runt homology domain and contain divergent sequences of unknown function N-terminal to this domain [41].
  • Small interfering RNA knockdown studies in osteoblasts validate that DLX3 is a potent regulator of Runx2 [42].
  • Compared with wild-type controls, osteocalcin mRNA was down-regulated in Apert osteoblasts, Runt-related transcription factor-2 (RUNX2) mRNA was differentially spliced, and FGF2 secretion was greater [43].
  • However analysis of the three-dimensional structure of the DNA binding runt domain of the RUNX proteins and its interaction with DNA, as well as the cofactor CBFB, start to provide an insight into how missense mutations affect RUNX2 function [44].

Analytical, diagnostic and therapeutic context of RUNX2

  • We show that signal transducers of transforming growth factor beta superfamily receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance the transactivation ability of this factor [45].
  • Finally, co-immunoprecipitation assays detected a physical complex containing DLX5 and RUNX2 [19].
  • By using chromatin immunoprecipitation (ChIP) analysis in MC3T3-E1 (clone MC-4) preosteoblast cells, RUNX2 was shown to bind a chromatin fragment containing the proximal Bsp promoter [19].
  • In these 264 subjects, we identified 16 allelic variations within the RUNX2 gene and promoters (P1 and P2) through DNA sequencing and denaturing high-performance liquid chromatography [46].
  • It is possible that taxol-induced acute depletion of the nuclear levels of RUNX2 and/or other cell growth regulatory factors may represent an alternative pathway by which taxol exerts its biological effects during cancer chemotherapies [22].


  1. Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations. Yoshida, T., Kanegane, H., Osato, M., Yanagida, M., Miyawaki, T., Ito, Y., Shigesada, K. Am. J. Hum. Genet. (2002) [Pubmed]
  2. Dominance of SOX9 function over RUNX2 during skeletogenesis. Zhou, G., Zheng, Q., Engin, F., Munivez, E., Chen, Y., Sebald, E., Krakow, D., Lee, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. Jin, Y.H., Jeon, E.J., Li, Q.L., Lee, Y.H., Choi, J.K., Kim, W.J., Lee, K.Y., Bae, S.C. J. Biol. Chem. (2004) [Pubmed]
  4. Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. Sakakura, C., Hagiwara, A., Miyagawa, K., Nakashima, S., Yoshikawa, T., Kin, S., Nakase, Y., Ito, K., Yamagishi, H., Yazumi, S., Chiba, T., Ito, Y. Int. J. Cancer (2005) [Pubmed]
  5. Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Javed, A., Barnes, G.L., Pratap, J., Antkowiak, T., Gerstenfeld, L.C., van Wijnen, A.J., Stein, J.L., Lian, J.B., Stein, G.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Expression and function of Cbfa-1/Runx2 in thyroid papillary carcinoma cells. Endo, T., Ohta, K., Kobayashi, T. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  7. Suppression of androgen-independent prostate cancer cell aggressiveness by FTY720: validating Runx2 as a potential antimetastatic drug screening platform. Chua, C.W., Chiu, Y.T., Yuen, H.F., Chan, K.W., Man, K., Wang, X., Ling, M.T., Wong, Y.C. Clin. Cancer Res. (2009) [Pubmed]
  8. Crossed cerebellar diaschisis: analysis of iodine-123-IMP SPECT imaging. Flores, L.G., Futami, S., Hoshi, H., Nagamachi, S., Ohnishi, T., Jinnouchi, S., Watanabe, K. J. Nucl. Med. (1995) [Pubmed]
  9. Fly-like visuomotor responses of a robot using aVLSI motion-sensitive chips. Liu, S.C., Usseglio-Viretta, A. Biological cybernetics. (2001) [Pubmed]
  10. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Dobreva, G., Chahrour, M., Dautzenberg, M., Chirivella, L., Kanzler, B., Fariñas, I., Karsenty, G., Grosschedl, R. Cell (2006) [Pubmed]
  11. Core-binding factor beta interacts with Runx2 and is required for skeletal development. Yoshida, C.A., Furuichi, T., Fujita, T., Fukuyama, R., Kanatani, N., Kobayashi, S., Satake, M., Takada, K., Komori, T. Nat. Genet. (2002) [Pubmed]
  12. Cbfbeta interacts with Runx2 and has a critical role in bone development. Kundu, M., Javed, A., Jeon, J.P., Horner, A., Shum, L., Eckhaus, M., Muenke, M., Lian, J.B., Yang, Y., Nuckolls, G.H., Stein, G.S., Liu, P.P. Nat. Genet. (2002) [Pubmed]
  13. Tissue-wide expression profiling using cDNA subtraction and microarrays to identify tumor-specific genes. Amatschek, S., Koenig, U., Auer, H., Steinlein, P., Pacher, M., Gruenfelder, A., Dekan, G., Vogl, S., Kubista, E., Heider, K.H., Stratowa, C., Schreiber, M., Sommergruber, W. Cancer Res. (2004) [Pubmed]
  14. Induction of retinoic acid-binding protein in normal and malignant human myeloid cells by retinoic acid in acute promyelocytic leukemia patients. Cornic, M., Delva, L., Guidez, F., Balitrand, N., Degos, L., Chomienne, C. Cancer Res. (1992) [Pubmed]
  15. The use of the L-plastin promoter for adenoviral-mediated, tumor-specific gene expression in ovarian and bladder cancer cell lines. Peng, X.Y., Won, J.H., Rutherford, T., Fujii, T., Zelterman, D., Pizzorno, G., Sapi, E., Leavitt, J., Kacinski, B., Crystal, R., Schwartz, P., Deisseroth, A. Cancer Res. (2001) [Pubmed]
  16. In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia. Cornic, M., Delva, L., Castaigne, S., Lefebvre, P., Balitrand, N., Degos, L., Chomienne, C. Leukemia (1994) [Pubmed]
  17. In vitro all-trans retinoic acid (ATRA) sensitivity and cellular retinoic acid binding protein (CRABP) levels in relapse leukemic cells after remission induction by ATRA in acute promyelocytic leukemia. Cornic, M., Delva, L., Castaigne, S., Lefebvre, P., Balitrand, N., Degos, L., Chomienne, C. Leukemia (1994) [Pubmed]
  18. Characterization of a new syndrome that associates craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, and skin eruption: CDAGS. Mendoza-Londono, R., Lammer, E., Watson, R., Harper, J., Hatamochi, A., Hatamochi-Hayashi, S., Napierala, D., Hermanns, P., Collins, S., Roa, B.B., Hedge, M.R., Wakui, K., Nguyen, D., Stockton, D.W., Lee, B. Am. J. Hum. Genet. (2005) [Pubmed]
  19. Cooperative interactions between RUNX2 and homeodomain protein-binding sites are critical for the osteoblast-specific expression of the bone sialoprotein gene. Roca, H., Phimphilai, M., Gopalakrishnan, R., Xiao, G., Franceschi, R.T. J. Biol. Chem. (2005) [Pubmed]
  20. Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Akt-independent signaling pathway. Qiao, M., Shapiro, P., Kumar, R., Passaniti, A. J. Biol. Chem. (2004) [Pubmed]
  21. Runt-related gene 2 in endothelial cells: inducible expression and specific regulation of cell migration and invasion. Sun, L., Vitolo, M., Passaniti, A. Cancer Res. (2001) [Pubmed]
  22. Microtubule-dependent nuclear-cytoplasmic shuttling of Runx2. Pockwinse, S.M., Rajgopal, A., Young, D.W., Mujeeb, K.A., Nickerson, J., Javed, A., Redick, S., Lian, J.B., van Wijnen, A.J., Stein, J.L., Stein, G.S., Doxsey, S.J. J. Cell. Physiol. (2006) [Pubmed]
  23. Basic fibroblast growth factor autocrine loop controls human osteosarcoma phenotyping and differentiation. Bodo, M., Lilli, C., Bellucci, C., Carinci, P., Calvitti, M., Pezzetti, F., Stabellini, G., Bellocchio, S., Balducci, C., Carinci, F., Baroni, T. Mol. Med. (2002) [Pubmed]
  24. Upstream and downstream targets of RUNX proteins. Otto, F., Lübbert, M., Stock, M. J. Cell. Biochem. (2003) [Pubmed]
  25. Serine phosphorylation of RUNX2 with novel potential functions as negative regulatory mechanisms. Wee, H.J., Huang, G., Shigesada, K., Ito, Y. EMBO Rep. (2002) [Pubmed]
  26. MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2. Pelletier, N., Champagne, N., Stifani, S., Yang, X.J. Oncogene (2002) [Pubmed]
  27. Reconstitution of Runx2/Cbfa1-null cells identifies a requirement for BMP2 signaling through a Runx2 functional domain during osteoblast differentiation. Bae, J.S., Gutierrez, S., Narla, R., Pratap, J., Devados, R., van Wijnen, A.J., Stein, J.L., Stein, G.S., Lian, J.B., Javed, A. J. Cell. Biochem. (2007) [Pubmed]
  28. The mechanisms of uremic serum-induced expression of bone matrix proteins in bovine vascular smooth muscle cells. Chen, N.X., Duan, D., O'Neill, K.D., Wolisi, G.O., Koczman, J.J., Laclair, R., Moe, S.M. Kidney Int. (2006) [Pubmed]
  29. Structural and functional characterization of Runx1, CBF beta, and CBF beta-SMMHC. Zhang, L., Lukasik, S.M., Speck, N.A., Bushweller, J.H. Blood Cells Mol. Dis. (2003) [Pubmed]
  30. A role for fibroblast growth factor receptor-2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the Saethre-Chotzen syndrome. Guenou, H., Kaabeche, K., Mée, S.L., Marie, P.J. Hum. Mol. Genet. (2005) [Pubmed]
  31. Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation. Qiao, M., Shapiro, P., Fosbrink, M., Rus, H., Kumar, R., Passaniti, A. J. Biol. Chem. (2006) [Pubmed]
  32. Effect of carnosine on runt-related transcription factor-2/core binding factor alpha-1 and Sox9 expressions of human periodontal ligament cells. Ito-Kato, E., Suzuki, N., Maeno, M., Takada, T., Tanabe, N., Takayama, T., Ito, K., Otsuka, K. J. Periodont. Res. (2004) [Pubmed]
  33. Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation. D'Alonzo, R.C., Selvamurugan, N., Karsenty, G., Partridge, N.C. J. Biol. Chem. (2002) [Pubmed]
  34. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. Franceschi, R.T., Xiao, G. J. Cell. Biochem. (2003) [Pubmed]
  35. The bone-specific transcriptional regulator Cbfa1 is a target of mechanical signals in osteoblastic cells. Ziros, P.G., Gil, A.P., Georgakopoulos, T., Habeos, I., Kletsas, D., Basdra, E.K., Papavassiliou, A.G. J. Biol. Chem. (2002) [Pubmed]
  36. Identification of cis and trans-acting transcriptional regulators in chondroinduced fibroblasts from the pre-phenotypic gene expression profile. Yates, K.E. Gene (2006) [Pubmed]
  37. Intimate relationship between TGF-beta/BMP signaling and runt domain transcription factor, PEBP2/CBF. Bae, S.C., Lee, K.S., Zhang, Y.W., Ito, Y. The Journal of bone and joint surgery. American volume. (2001) [Pubmed]
  38. The promyelotic leukemia zinc finger promotes osteoblastic differentiation of human mesenchymal stem cells as an upstream regulator of CBFA1. Ikeda, R., Yoshida, K., Tsukahara, S., Sakamoto, Y., Tanaka, H., Furukawa, K., Inoue, I. J. Biol. Chem. (2005) [Pubmed]
  39. Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type X collagen gene. Higashikawa, A., Saito, T., Ikeda, T., Kamekura, S., Kawamura, N., Kan, A., Oshima, Y., Ohba, S., Ogata, N., Takeshita, K., Nakamura, K., Chung, U.I., Kawaguchi, H. Arthritis Rheum. (2009) [Pubmed]
  40. Regulation of tissue inhibitor of metalloproteinase 1 gene transcription by RUNX1 and RUNX2. Bertrand-Philippe, M., Ruddell, R.G., Arthur, M.J., Thomas, J., Mungalsingh, N., Mann, D.A. J. Biol. Chem. (2004) [Pubmed]
  41. Identification of an N-terminal transactivation domain of Runx1 that separates molecular function from global differentiation function. Liu, H., Carlsson, L., Grundström, T. J. Biol. Chem. (2006) [Pubmed]
  42. BMP2 Commitment to the Osteogenic Lineage Involves Activation of Runx2 by DLX3 and a Homeodomain Transcriptional Network. Hassan, M.Q., Tare, R.S., Lee, S.H., Mandeville, M., Morasso, M.I., Javed, A., van Wijnen, A.J., Stein, J.L., Stein, G.S., Lian, J.B. J. Biol. Chem. (2006) [Pubmed]
  43. P253R fibroblast growth factor receptor-2 mutation induces RUNX2 transcript variants and calvarial osteoblast differentiation. Baroni, T., Carinci, P., Lilli, C., Bellucci, C., Aisa, M.C., Scapoli, L., Volinia, S., Carinci, F., Pezzetti, F., Calvitti, M., Farina, A., Conte, C., Bodo, M. J. Cell. Physiol. (2005) [Pubmed]
  44. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Otto, F., Kanegane, H., Mundlos, S. Hum. Mutat. (2002) [Pubmed]
  45. A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Zhang, Y.W., Yasui, N., Ito, K., Huang, G., Fujii, M., Hanai, J., Nogami, H., Ochi, T., Miyazono, K., Ito, Y. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  46. Association of functionally different RUNX2 P2 promoter alleles with BMD. Doecke, J.D., Day, C.J., Stephens, A.S., Carter, S.L., van Daal, A., Kotowicz, M.A., Nicholson, G.C., Morrison, N.A. J. Bone Miner. Res. (2006) [Pubmed]
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