Regulation of RUNX2 expression and activity (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: FBXW7a (Kumar et al. 2015), 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). View original pathway at:Reactome.
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: FBXW7a (Kumar et al. 2015), 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). View original pathway at:Reactome.
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Transcription of RUNX2 is stimulated by binding of TWIST1 transcription factor to the E1-box in the proximal P2 promoter of RUNX2 (Yang et al. 2011).
Studies in mice have shown that RUNX2-P2 can autoactivate its own expression by binding to the proximal P2 promoter of the RUNX2 gene (Ducy et al. 1999).
Based on studies in mice, 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). The complex of DEXA and NR3C1 may also inhibit RUNX2 activity by directly binding to the RUNX2 protein (Koromila et al. 2013).
Based on studies in mice, transcription of RUNX2 from the distal (P1) promoter is directly stimulated by DLX5 (and possibly DLX6). Binding of DLX5 to the RUNX2 promoter is antagonized by MSX2. Once bound to the RUNX2 promoter, MSX2 inhibits RUNX2 transcription (Lee et al. 2005). DLX5 is activated by BMP2 signaling through an unknown mechanism.
Transcription of RUNX2 from the P1 promoter may be inhibited by the transcriptional repressor GFI1, which is essential for hematopoiesis (D'Souza et al. 2011).
Dlx5 deficient mice show a mild delay in ossification of long bones and close to normal Runx2 expression. Mice that are double knockouts for Dlx5 and Dlx6 genes show severe defects in the formation of limbs, cranium and axial skeleton and die after birth. Dlx5/6 double knockouts show reduction in the number of Runx2-expressing chondrocytes (Robledo et al. 2002). As DLX6 is suggested by several studies to be redundant with DLX5 in the regulation of RUNX2 expression (Robledo et al. 2002, Holleville et al. 2007, Barron et al. 2011), although direct binding of DLX6 to the RUNX2 gene promoter has not been tested, DLX6 is shown as a candidate transcriptional regulator of RUNX2.