RUNX2

Identifiers

RUNX2, AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD, OSF-2, OSF2, PEA2aA, PEBP2aA, runt related transcription factor 2

External IDs

OMIM: 600211 MGI: 99829 HomoloGene: 68389 GeneCards: RUNX2

Gene ontology
Molecular function	• DNA binding • protein domain specific binding • transcription factor activity, sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • chromatin binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding • bHLH transcription factor binding • protein binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • transcription regulatory region DNA binding • repressing transcription factor binding • ATP binding • RNA polymerase II core promoter sequence-specific DNA binding
Cellular component	• cytoplasm • transcription factor complex • nucleoplasm • nuclear chromatin • nucleus
Biological process	• skeletal system development • hemopoiesis • regulation of transcription, DNA-templated • negative regulation of smoothened signaling pathway • chondrocyte differentiation • ossification • regulation of transcription from RNA polymerase II promoter • regulation of fibroblast growth factor receptor signaling pathway • skeletal system morphogenesis • chondrocyte development • cellular response to BMP stimulus • endochondral ossification • regulation of odontogenesis of dentin-containing tooth • cell maturation • transcription from RNA polymerase II promoter • BMP signaling pathway • stem cell differentiation • transcription, DNA-templated • positive regulation of transcription, DNA-templated • odontogenesis of dentin-containing tooth • T cell differentiation • positive regulation of gene expression • positive regulation of osteoblast differentiation • regulation of osteoblast differentiation • positive regulation of chondrocyte differentiation • osteoblast differentiation • neuron differentiation • positive regulation of cell proliferation • regulation of cell differentiation • osteoblast development • embryonic cranial skeleton morphogenesis • regulation of ossification • negative regulation of transcription, DNA-templated • embryonic forelimb morphogenesis • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus • osteoblast fate commitment
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_001024630 NM_001278478 NM_004348

NM_001145920 NM_001146038 NM_001271627 NM_001271630 NM_001271631
NM_001271633 NM_009820

RefSeq (protein)


NP_001015051.3 NP_001019801.3


NP_001139510.1 NP_001258556.1 NP_033950.2

Location (UCSC)

Chr 6: 45.33 – 45.66 Mb

Chr 17: 44.5 – 44.81 Mb

PubMed search

^[1]

^[2]

Wikidata

View/Edit Human

View/Edit Mouse

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.^[3]

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.^[4]

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.^[5]

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. ^[6]

Interactions

RUNX2 has been shown to interact with:

miR-133 directly inhibits Runx2.^[16]

References

↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ "Entrez Gene: RUNX2 runt-related transcription factor 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
1 2 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.
1 2 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.
↑ 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.
↑ 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.
1 2 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.
1 2 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.
↑ 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.
↑ 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.

External links

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

PDB gallery

1cmo: IMMUNOGLOBULIN MOTIF DNA-RECOGNITION AND HETERODIMERIZATION FOR THE PEBP2/CBF RUNT-DOMAIN

1co1: FOLD OF THE CBFA

1e50: AML1/CBF COMPLEX

1h9d: AML1/CBF-BETA/DNA COMPLEX

1hjb: CRYSTAL STRUCTURE OF RUNX-1/AML1/CBFALPHA RUNT DOMAIN AND C/EBPBETA BZIP DIMERIC BOUND TO A DNA FRAGMENT FROM THE CSF-1R PROMOTER

1hjc: CRYSTAL STRUCTURE OF RUNX-1/AML1/CBFALPHA RUNT DOMAIN BOUND TO A DNA FRAGMENT FROM THE CSF-1R PROMOTER

1io4: CRYSTAL STRUCTURE OF RUNX-1/AML1/CBFALPHA RUNT DOMAIN-CBFBETA CORE DOMAIN HETERODIMER AND C/EBPBETA BZIP HOMODIMER BOUND TO A DNA FRAGMENT FROM THE CSF-1R PROMOTER

1ljm: DNA recognition is mediated by conformational transition and by DNA bending

Transcription factors and intracellular receptors

(1) Basic domains

(1.1) Basic leucine zipper (bZIP)	Activating transcription factor AATF 1 2 3 4 5 6 7 AP-1 c-Fos FOSB FOSL1 FOSL2 JDP2 c-Jun JUNB JunD BACH 1 2 BATF BLZF1 C/EBP α β γ δ ε ζ CREB 1 3 L1 CREM DBP DDIT3 GABPA HLF MAF B F G K NFE 2 L1 L2 L3 NFIL3 NRL NRF 1 2 3 XBP1

(1.2) Basic helix-loop-helix (bHLH)	ATOH1 AhR AHRR ARNT ASCL1 BHLH 2 3 9 ARNTL ARNTL ARNTL2 CLOCK EPAS1 FIGLA HAND 1 2 HES 5 6 HEY 1 2 L HES1 HIF 1A 3A ID 1 2 3 4 LYL1 MESP2 MXD4 MYCL1 MYCN Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 Neurogenins 1 2 3 NeuroD 1 2 NPAS 1 2 3 OLIG 1 2 Pho4 Scleraxis SIM 1 2 TAL 1 2 Twist USF1

(1.3) bHLH-ZIP	AP-4 MAX MXD3 MITF MNT MLX MXI1 Myc SREBP 1 2

(1.4) NF-1	NFI A B C X SMAD R-SMAD 1 2 3 5 9 I-SMAD 6 7 4)

(1.5) RF-X	RFX 1 2 3 4 5 6 ANK

(1.6) Basic helix-span-helix (bHSH)	AP-2 α β γ δ ε

(2) Zinc finger DNA-binding domains

(2.1) Nuclear receptor (Cys₄)

subfamily 1	Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR

subfamily 2	COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX

subfamily 3	Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ

subfamily 4	NUR NGFIB NOR1 NURR1

subfamily 5	LRH-1 SF1

subfamily 6	GCNF

subfamily 0	DAX1 SHP

(2.2) Other Cys₄

GATA
- 1
- 2
- 3
- 4
- 5
- 6
MTA
- 1
- 2
- 3
TRPS1

(2.3) Cys₂His₂

General transcription factors
- TFIIA
- TFIIB
- TFIID
- TFIIE
  - 1
  - 2
- TFIIF
- 1
- 2
  - TFIIH
  - 1
  - 2
  - 4
  - 2I
  - 3A
  - 3C1
  - 3C2

ATBF1
BCL
- 6
- 11A
- 11B
CTCF
E4F1
EGR
- 1
- 2
- 3
- 4
ERV3
GFI1
GLI-Krüppel family
- 1
- 2
- 3
- REST
- S1
- S2
- YY1
HIC
- 1
- 2
HIVEP
- 1
- 2
- 3
IKZF
- 1
- 2
- 3
ILF
- 2
- 3
KLF
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10
- 11
- 12
- 13
- 14
- 15
- 17
MTF1
MYT1
OSR1
PRDM9
SALL
- 1
- 2
- 3
- 4
SP
- 1
- 2
- 4
- 7
- 8
TSHZ3
WT1
Zbtb7
- 7A
- 7B
ZBTB
- 11
- 16
- 17
- 20
- 32
- 33
- 40
zinc finger
- 3
- 7
- 9
- 10
- 19
- 22
- 24
- 33B
- 34
- 35
- 41
- 43
- 44
- 51
- 74
- 143
- 146
- 148
- 165
- 202
- 217
- 219
- 238
- 239
- 259
- 267
- 268
- 281
- 295
- 300
- 318
- 330
- 346
- 350
- 365
- 366
- 384
- 423
- 451
- 452
- 471
- 593
- 638
- 644
- 649
- 655

(2.4) Cys₆

HIVEP1

(2.5) Alternating composition

AIRE
DIDO1
GRLF1
ING
- 1
- 2
- 4
JARID
- 1A
- 1B
- 1C
- 1D
- 2
JMJD1B

(2.6) WRKY

WRKY

(3) Helix-turn-helix domains

(3.1) Homeodomain	ARX CDX 1 2 CRX CUTL1 DBX 1 2 DLX 3 4 5 EMX 1 2 EN 1 2 FHL 1 2 3 HESX1 HHEX HLX Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 HOPX IRX 1 2 3 4 5 6 MKX LMX 1A 1B MEIS 1 2 MEOX2 MNX1 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 6-1 6-2 NOBOX PBX 1 2 3 PHF 1 3 6 8 10 16 17 20 21A PHOX 2A 2B PITX 1 2 3 POU domain PIT-1 BRN-3: A B C Octamer transcription factor: 1 2 3/4 6 7 11 OTX 1 2 PDX1 SATB2 SHOX2 SIX 1 2 3 4 5 VAX1 ZEB 1 2

(3.2) Paired box	PAX 1 2 3 4 5 6 7 8 9 PRRX 1 2 RAX

(3.3) Fork head / winged helix	E2F 1 2 3 4 5 FOX proteins A1 A2 A3 C1 C2 D3 D4 E1 E3 F1 G1 H1 I1 J1 J2 K1 K2 L2 M1 N1 N3 O1 O3 O4 P1 P2 P3 P4

(3.4) Heat shock factors	HSF 1 2 4

(3.5) Tryptophan clusters	ELF 2 4 5 EGF ELK 1 3 4 ERF ETS 1 2 ERG SPIB ETV 1 4 5 6 FLI1 Interferon regulatory factors 1 2 3 4 5 6 7 8 MYB MYBL2

(3.6) TEA domain	transcriptional enhancer factor 1 2 3 4

(4) β-Scaffold factors with minor groove contacts

(4.1) Rel homology region	NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5

(4.2) STAT	STAT 1 2 3 4 5 6

(4.3) p53	p53 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF TP63

(4.4) MADS box	Mef2 A B C D SRF

(4.6) TATA-binding proteins	TBP TBPL1

(4.7) High-mobility group	BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B LEF1 SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 18 21 SRY SSRP1 TCF 3 4 TOX 1 2 3 4

(4.9) Grainyhead	TFCP2

(4.10) Cold-shock domain	CSDA YBX1

(4.11) Runt	CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1

(0) Other transcription factors

(0.2) HMGI(Y)	HMGA 1 2 HBP1

(0.3) Pocket domain	Rb RBL1 RBL2

(0.5) AP-2/EREBP-related factors	Apetala 2 EREBP B3

(0.6) Miscellaneous	ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma

see also transcription factor/coregulator deficiencies

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