Regulation of RUNX2 expression and activity

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Homo sapiens
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Several transcription factors have been implicated in regulation of the RUNX2 gene transcription. Similar to the RUNX1 gene, the RUNX2 gene expression can be regulated from the proximal P2 promoter or the distal P1 promoter (reviewed in Li and Xiao 2007).
Activated estrogen receptor alpha (ESR1) binds estrogen response elements (EREs) in the P2 promoter and stimulates RUNX2 transcription (Kammerer et al. 2013). Estrogen-related receptor alpha (ERRA) binds EREs or estrogen-related response elements (ERREs) in the P2 promoter of RUNX2. When ERRA is bound to its co-factor PPARG1CA (PGC1A), it stimulates RUNX2 transcription. When bound to its co-factor PPARG1CB (PGC1B), ERRA represses RUNX2 transcription (Kammerer et al. 2013).
TWIST1, a basic helix-loop-helix (bHLH) transcription factor, stimulates RUNX2 transcription by binding to the E1-box in the P2 promoter (Yang, Yang et al. 2011). TWIST proteins also interact with the DNA-binding domain of RUNX2 to modulate its activity during skeletogenesis (Bialek et al. 2004). Schnurri-3 (SHN3) is another protein that interacts with RUNX2 to decrease its availability in the nucleus and therefore its activity (Jones et al. 2006). In contrast, RUNX2 and SATB2 interact to enhance the expression of osteoblast-specific genes (Dobreva et al. 2006). Formation of the heterodimer with CBFB (CBF-beta) also enhances the transcriptional activity of RUNX2 (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002).
Transcription of RUNX2 from the proximal promoter is inhibited by binding of the glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) to a glucocorticoid receptor response element (GRE), which is also present in the human promoter (Zhang et al. 2012).
NKX3-2 (BAPX1), required for embryonic development of the axial skeleton (Tribioli and Lufkin 1999), binds the distal (P1) promoter of the RUNX2 gene and inhibits its transcription (Lengner et al. 2005). RUNX2-P1 transcription is also autoinhibited by RUNX2-P1, which binds to RUNX2 response elements in the P1 promoter of RUNX2 (Drissi et al. 2000). In contrast, binding of RUNX2-P2 to the proximal P2 promoter autoactivates transcription of RUNX2-P2 (Ducy et al. 1999). Binding of a homeodomain transcription factor DLX5, and possibly DLX6, to the RUNX2 P1 promoter stimulates RUNX2 transcription (Robledo et al. 2002, Lee et al. 2005). The homeobox transcription factor MSX2 can bind to DLX5 sites in the promoter of RUNX2 and inhibit transcription of RUNX2-P1 (Lee et al. 2005).
Translocation of RUNX2 protein to the nucleus is inhibited by binding to non-activated STAT1 (Kim et al. 2003).
Several E3 ubiquitin ligases were shown to polyubiquitinate RUNX2, targeting it for proteasome-mediated degradation: STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016).
Literature References
PubMed ID Title Journal Year
16751105 SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation

Chahrour, M, Chirivella, L, Fariñas, I, Karsenty, G, Kanzler, B, Dobreva, G, Dautzenberg, M, Grosschedl, R

Cell 2006
21931630 Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST

Yang, DC, Hung, SC, Tsai, CC, Chen, YH, Yang, MH, Huang, TF

PLoS ONE 2011
15030764 A twist code determines the onset of osteoblast differentiation

Yang, X, Ornitz, DM, Kern, B, Yu, K, Wu, H, Schrock, M, Justice, MJ, Olson, EN, Karsenty, G, Sosic, D, Bialek, P, Hong, N

Dev. Cell 2004
26778333 Skp2 inhibits osteogenesis by promoting ubiquitin-proteasome degradation of Runx2

Khan, MP, Kumar, Y, Trivedi, AK, Kanaujiya, JK, Kapoor, I, Sanyal, S, Thacker, G, Chattopadhyay, N, Lochab, S, Ahmed, S, Shukla, N

Biochim. Biophys. Acta 2016
23403054 Estrogen Receptor α (ERα) and Estrogen Related Receptor α (ERRα) are both transcriptional regulators of the Runx2-I isoform

Gutzwiller, S, Kammerer, M, Fournier, B, Stauffer, D, Delhon, I, Seltenmeyer, Y

Mol. Cell. Endocrinol. 2013
12923053 Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation

Koga, T, Chin, YE, Kim, S, Takayanagi, H, Yokochi, T, Isobe, M, Karsenty, G, Kern, BE, Taniguchi, T

Genes Dev. 2003
15703179 Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation

van Wijnen, AJ, Lengner, CJ, Lian, JB, Stein, JL, Stein, GS, Lepper, C, Hassan, MQ, Serra, RW

J. Biol. Chem. 2005
25260729 A feedback loop between RUNX2 and the E3 ligase SMURF1 in regulation of differentiation of human dental pulp stem cells

Guan, L, Yang, F, Lu, Q, Zhang, Y, Li, D, Zhang, X, Xu, N, He, Y

J Endod 2014
12434152 Core-binding factor beta interacts with Runx2 and is required for skeletal development

Kanatani, N, Fujita, T, Komori, T, Satake, M, Takada, K, Yoshida, CA, Fukuyama, R, Kobayashi, S, Furuichi, T

Nat. Genet. 2002
16115867 Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter

Choi, KY, Lee, MH, Cho, JY, Wozney, JM, Hwang, YS, Kim, YJ, Choi, JY, Bae, SC, Ryoo, HM, Chi, XZ, Kim, BG, Kim, JI, Yoon, WJ

J. Biol. Chem. 2005
18541707 CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation

Ren, F, Shi, Y, Zhai, Y, Irwin, DM, Li, X, Chang, Z, Shang, Y, Zheng, H, Huang, M, Chen, D, Wang, Y

J. Cell Biol. 2008
22422618 Down-regulation of type I Runx2 mediated by dexamethasone is required for 3T3-L1 adipogenesis

Huang, HY, Guo, L, He, Q, Liu, Y, Qian, SW, Ma, CG, Zhang, YY, Tang, QQ, Li, X

Mol. Endocrinol. 2012
12000792 The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development

Li, X, Robledo, RF, Rajan, L, Lufkin, T

Genes Dev. 2002
16901655 Advances in Runx2 regulation and its isoforms

Xiao, ZS, Li, YL

Med. Hypotheses 2007
12434156 Cbfbeta interacts with Runx2 and has a critical role in bone development

Muenke, M, Jeon, JP, Liu, PP, Yang, Y, Horner, A, Javed, A, Shum, L, Lian, JB, Kundu, M, Stein, GS, Eckhaus, M, Nuckolls, GH

Nat. Genet. 2002
11857736 Mutations in the RUNX2 gene in patients with cleidocranial dysplasia

Mundlos, S, Otto, F, Kanegane, H

Hum. Mutat. 2002
16728642 Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3

Glimcher, LH, Oukka, M, Wein, MN, Hofstaetter, JG, Jones, DC, Glimcher, MJ

Science 2006
10215629 A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development

Geoffroy, V, Priemel, M, Karsenty, G, Starbuck, M, Ducy, P, Pinero, G, Amling, M, Shen, J

Genes Dev. 1999
10911365 Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene

Jones, S, Luc, Q, Stein, JL, Stein, GS, Choi, JY, Neil, JC, Hu, M, Van Wijnen, AJ, Terry, A, Drissi, H, Shakoori, R, Chuva De Sousa Lopes, S, Lian, JB

J. Cell. Physiol. 2000
12738770 E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteoblast differentiation

Oyajobi, BO, Qiao, M, Zhao, M, Mundy, GR, Chen, D

J. Biol. Chem. 2003
10572046 The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen

Tribioli, C, Lufkin, T

Development 1999
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