RUNX2 表达和活性的调节
中文名称
通路描述
多个转录因子涉及 RUNX2 基因转录的调节。与 RUNX1 基因类似，RUNX2 基因表达可从近端 P2 启动子或远端 P1 启动子调节（综述 Li 和 Xiao 2007）。激活的雌激素受体 alpha（ESR1）结合 P2 启动子中的雌激素反应元件（EREs），刺激 RUNX2 转录（Kammerer et al. 2013）。雌激素相关受体 alpha（ERRA）结合 RUNX2 的 P2 启动子中的 EREs 或雌激素相关反应元件（ERREs）。当 ERRA 与其协同因子 PPARG1CA（PGC1A）结合时，它刺激 RUNX2 转录。当与 PPARG1CB（PGC1B）结合时，ERRA 抑制 RUNX2 转录（Kammerer et al. 2013）。TWIST1，一种碱性螺旋 - 环 - 螺旋（bHLH）转录因子，通过结合 P2 启动子中的 E1 盒刺激 RUNX2 转录（Yang, Yang et al. 2011）。TWIST 蛋白还与 RUNX2 的 DNA 结合域相互作用，调节其活性，特别是在骨形成过程中（Bialek et al. 2004）。Schnurri-3（SHN3）是另一个与 RUNX2 相互作用的蛋白，通过与 RUNX2 结合减少其在细胞核中的可用性，从而抑制其活性（Jones et al. 2006）。与 SATB2 结合时，RUNX2 可增强成骨细胞特异性基因的表达（Dobreva et al. 2006）。与 CBFB（CBF-beta）形成异二聚体也增强 RUNX2 的转录活性（Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002）。RUNX2 从近端启动子的转录被 dexamethasone（DEXA）激活的糖皮质激素受体（NR3C1）结合到糖皮质激素受体反应元件（GRE）抑制，该元件也存在于人类启动子中（Zhang et al. 2012）。NKX3-2（BAPX1），对于胚胎轴向骨骼发育所需，结合 RUNX2 基因的远端（P1）启动子并抑制其转录（Lengner et al. 2005）。RUNX2-P1 转录也通过 RUNX2-P1 与 RUNX2 反应元件在 RUNX2 的 P1 启动子结合而自抑制（Drissi et al. 2000）。与近端 P2 启动子结合 RUNX2-P2 自激活 RUNX2-P2 的转录（Ducy et al. 1999）。结合 homeodomain 转录因子 DLX5 和可能 DLX6 到 RUNX2 P1 启动子刺激 RUNX2 转录（Robledo et al. 2002, Lee et al. 2005）。homeobox 转录因子 MSX2 可结合 RUNX2 启动子中的 DLX5 位点并抑制 RUNX2-P1 的转录（Lee et al. 2005）。RUNX2 蛋白转位到细胞核被非激活的 STAT1 结合抑制（Kim et al. 2003）。多个 E3 泛素连接酶被证明多泛素化 RUNX2，将其靶向蛋白酶体介导的降解：STUB1（CHIP）（Li et al. 2008）、SMURF1（Zhao et al. 2003, Yang et al. 2014）、WWP1（Jones et al. 2006）和 SKP2（Thacker et al. 2016）。
英文描述
Regulation of RUNX2 expression and activity 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).
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).
所含基因
61 个基因
ADRM1
BMP2
CBFB
CUL1
DLX5
DLX6
ESR1
ESRRA
GSK3B
HIVEP3
MSX2
NR3C1
P1
P2
PPARGC1A
PPARGC1B
PSMA1
PSMA2
PSMA3
PSMA4
PSMA5
PSMA6
PSMA7
PSMB1
PSMB2
PSMB3
PSMB4
PSMB5
PSMB6
PSMB7
PSMC1
PSMC2
PSMC3
PSMC4
PSMC5
PSMC6
PSMD1
PSMD11
PSMD12
PSMD13
PSMD14
PSMD2
PSMD3
PSMD6
PSMD7
PSMD8
RBX1
RPS27A
RUNX2-P1
RUNX2-P2
SEM1
SKP1
SKP2
SMURF1
STAT1
STUB1
TWIST1
UBA52
UBB
UBC
WWP1