RUNX2

Runt-related transcription factor 2
PDB rendering based on 1cmo.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1cmo​, 1co1​, 1e50​, 1h9d​, 1hjb​, 1hjc​, 1io4​, 1ljm​
Identifiers
Symbols	RUNX2 ; AML3; CBF-alpha-1; CBFA1; CCD; CCD1; CLCD; OSF-2; OSF2; PEA2aA; PEBP2aA
External IDs	OMIM: 600211 MGI: 99829 HomoloGene: 68389 GeneCards: RUNX2 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II core promoter sequence-specific DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • protein binding • ATP binding • protein domain specific binding • histone deacetylase binding • bHLH transcription factor binding • repressing transcription factor binding Cellular component • nuclear chromatin • nucleoplasm • transcription factor complex • cytoplasm Biological process • ossification • osteoblast differentiation • endochondral ossification • osteoblast fate commitment • chondrocyte differentiation • chondrocyte development • osteoblast development • regulation of transcription from RNA polymerase II promoter • transcription initiation from RNA polymerase II promoter • positive regulation of cell proliferation • gene expression • hemopoiesis • neuron differentiation • T cell differentiation • BMP signaling pathway • positive regulation of chondrocyte differentiation • embryonic forelimb morphogenesis • regulation of fibroblast growth factor receptor signaling pathway • odontogenesis of dentin-containing tooth • regulation of odontogenesis of dentin-containing tooth • cellular response to fibroblast growth factor stimulus • regulation of cell differentiation • positive regulation of osteoblast differentiation • negative regulation of smoothened signaling pathway • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • cell maturation • embryonic cranial skeleton morphogenesis • stem cell differentiation • cellular response to BMP stimulus • positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	860	12393
Ensembl	ENSG00000124813	ENSMUSG00000039153
UniProt	Q13950	Q08775
RefSeq (mRNA)	NM_001015051	NM_001145920
RefSeq (protein)	NP_001015051	NP_001139392
Location (UCSC)	Chr 6: 45.33 – 45.66 Mb	Chr 17: 44.5 – 44.81 Mb
PubMed search

Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the RUNX2 gene. RUNX2 is a key transcription factor associated with osteoblast differentiation.

Function

This protein is a member of the RUNX family of transcription factors and has a Runt DNA-binding domain. It is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Transcript variants of the gene that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing.^[1]

Differences in RUNX2 are hypothesized to be the cause of the skeletal differences between modern humans and early humans such as Neanderthals. These differences include a different shape of the skull, a bell-shaped chest in Neanderthals, etc.^[2]

The binding interactions of RUNX2 change as cells go through mitosis, with binding affinity increasing as chromosomes condense and then decreasing through subsequent mitotic phases. The increased residence of RUNX2 at mitotic chromosomes may reflect its epigenetic function in "bookmarking" of target genes in cancer cells.^[3]

Pathology

Mutations in Cbfa1/Runx2 are associated with the disease Cleidocranial dysostosis.

Co-factors

Runx proteins represent the alpha DNA binding subunit of a heteromeric protein complex that also includes the non-DNA binding beta-subunit which increases the DNA binding affinity of the alpha subunit. In addition, there is a large cohort of regulatory proteins that bind to the C-terminus of Runx2 to modify its transcriptional function. ^[4]

Interactions

RUNX2 has been shown to interact with:

• AR^[5]
• ER-α^[6]
• C-Fos,^[7][8]
• C-jun,^[7][8]
• HDAC3,^[9]
• MYST4,^[10]
• SMAD1^[11][12]
• SMAD3,^[11][12] and
• STUB1.^[13]

miR-133 directly inhibits Runx2.^[14]

See also

• RUNX1
• RUNX3

References

1. "Entrez Gene: RUNX2 runt-related transcription factor 2".
2. Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, Hansen NF, Durand EY, Malaspinas AS, Jensen JD, Marques-Bonet T, Alkan C, Prüfer K, Meyer M, Burbano HA, Good JM, Schultz R, Aximu-Petri A, Butthof A, Höber B, Höffner B, Siegemund M, Weihmann A, Nusbaum C, Lander ES, Russ C, Novod N, Affourtit J, Egholm M, Verna C, Rudan P, Brajkovic D, Kucan Z, Gusic I, Doronichev VB, Golovanova LV, Lalueza-Fox C, de la Rasilla M, Fortea J, Rosas A, Schmitz RW, Johnson PL, Eichler EE, Falush D, Birney E, Mullikin JC, Slatkin M, Nielsen R, Kelso J, Lachmann M, Reich D, Pääbo S (May 2010). "A draft sequence of the Neandertal genome". Science 328 (5979): 710–22. doi:10.1126/science.1188021. PMID 20448178.
3. Pockwinse SM, Kota KP, Quaresma AJ, Imbalzano AN, Lian JB, van Wijnen AJ, Stein JL, Stein GS, Nickerson JA (May 2011). "Live cell imaging of the cancer-related transcription factor RUNX2 during mitotic progression". Journal of Cellular Physiology 226 (5): 1383–9. doi:10.1002/jcp.22465. PMC 3050607. PMID 20945391.
4. Lian JB, Javed A, Zaidi SK, Lengner C, Montecino M, van Wijnen AJ, Stein JL, Stein GS (2004). "Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors". Critical Reviews in Eukaryotic Gene Expression 14 (1-2): 1–41. PMID 15104525.
5. Baniwal SK, Khalid O, Sir D, Buchanan G, Coetzee GA, Frenkel B (Aug 2009). "Repression of Runx2 by androgen receptor (AR) in osteoblasts and prostate cancer cells: AR binds Runx2 and abrogates its recruitment to DNA". Molecular Endocrinology 23 (8): 1203–14. doi:10.1210/me.2008-0470. PMC 2718746. PMID 19389811.
6. Khalid O, Baniwal SK, Purcell DJ, Leclerc N, Gabet Y, Stallcup MR, Coetzee GA, Frenkel B (Dec 2008). "Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer". Endocrinology 149 (12): 5984–95. doi:10.1210/en.2008-0680. PMC 2613062. PMID 18755791.
7. Hess J, Porte D, Munz C, Angel P (Jun 2001). "AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element". The Journal of Biological Chemistry 276 (23): 20029–38. doi:10.1074/jbc.M010601200. PMID 11274169.
8. D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC (Jan 2002). "Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation". The Journal of Biological Chemistry 277 (1): 816–22. doi:10.1074/jbc.M107082200. PMID 11641401.
9. Schroeder TM, Kahler RA, Li X, Westendorf JJ (Oct 2004). "Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation". The Journal of Biological Chemistry 279 (40): 41998–2007. doi:10.1074/jbc.M403702200. PMID 15292260.
10. Pelletier N, Champagne N, Stifani S, Yang XJ (Apr 2002). "MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2". Oncogene 21 (17): 2729–40. doi:10.1038/sj.onc.1205367. PMID 11965546.
11. Zhang YW, Yasui N, Ito K, Huang G, Fujii M, Hanai J, Nogami H, Ochi T, Miyazono K, Ito Y (Sep 2000). "A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia". Proceedings of the National Academy of Sciences of the United States of America 97 (19): 10549–54. doi:10.1073/pnas.180309597. PMC 27062. PMID 10962029.
12. Hanai J, Chen LF, Kanno T, Ohtani-Fujita N, Kim WY, Guo WH, Imamura T, Ishidou Y, Fukuchi M, Shi MJ, Stavnezer J, Kawabata M, Miyazono K, Ito Y (Oct 1999). "Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter". The Journal of Biological Chemistry 274 (44): 31577–82. doi:10.1074/jbc.274.44.31577. PMID 10531362.
13. Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y, Zhai Y, Irwin DM, Shi Y, Chen D, Chang Z (Jun 2008). "CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation". The Journal of Cell Biology 181 (6): 959–72. doi:10.1083/jcb.200711044. PMC 2426947. PMID 18541707.
14. Li Z, Hassan MQ, Volinia S, van Wijnen AJ, Stein JL, Croce CM, Lian JB, Stein GS (Sep 2008). "A microRNA signature for a BMP2-induced osteoblast lineage commitment program". Proceedings of the National Academy of Sciences of the United States of America 105 (37): 13906–11. doi:10.1073/pnas.0804438105. PMC 2544552. PMID 18784367.

Further reading

• Otto F, Kanegane H, Mundlos S (Mar 2002). "Mutations in the RUNX2 gene in patients with cleidocranial dysplasia". Human Mutation 19 (3): 209–16. doi:10.1002/humu.10043. PMID 11857736.
• Komori T (Mar 2002). "[Cbfa1/Runx2, an essential transcription factor for the regulation of osteoblast differentiation]". Nihon Rinsho. Japanese Journal of Clinical Medicine. 60 Suppl 3: 91–7. PMID 11979975.
• Stock M, Otto F (Jun 2005). "Control of RUNX2 isoform expression: the role of promoters and enhancers". Journal of Cellular Biochemistry 95 (3): 506–17. doi:10.1002/jcb.20471. PMID 15838892.
• Blyth K, Cameron ER, Neil JC (May 2005). "The RUNX genes: gain or loss of function in cancer". Nature Reviews. Cancer 5 (5): 376–87. doi:10.1038/nrc1607. PMID 15864279.
• Schroeder TM, Jensen ED, Westendorf JJ (Sep 2005). "Runx2: a master organizer of gene transcription in developing and maturing osteoblasts". Birth Defects Research. Part C, Embryo Today 75 (3): 213–25. doi:10.1002/bdrc.20043. PMID 16187316.
• Frenkel B, Hong A, Baniwal SK, Coetzee GA, Ohlsson C, Khalid O, Gabet Y (Aug 2010). "Regulation of adult bone turnover by sex steroids". Journal of Cellular Physiology 224 (2): 305–10. doi:10.1002/jcp.22159. PMID 20432458.

External links

• GeneReviews/NCBI/NIH/UW entry on Cleidocranial Dysplasia
• Runx2 protein at the US National Library of Medicine Medical Subject Headings (MeSH)