RUNX2 转录调控
中文名称
通路描述
RUNX2（CBFA1 或 AML3）转录因子，与其他 RUNX 家族成员 RUNX1 和 RUNX3 类似，可与 CBFB（CBF-beta）形成复合物（Kundu 等，2002；Yoshida 等，2002；Otto 等，2002）。RUNX2 主要调控与骨骼发育相关的基因的转录（综述于 Karsenty 2008）。RUNX2 通过调控成骨细胞分化和软骨细胞成熟，分别介导内骨化和外骨化发育。RUNX2 刺激 BGLAP 基因（Ducy 和 Karsenty 1995，Ducy 等 1997）的转录，该基因编码骨源性激素骨钙素（Osteocalcin），是骨细胞外基质中最丰富的非胶原蛋白之一（综述于 Karsenty 和 Olson 2016）。RUNX2 直接控制与成骨细胞分化和功能相关的基因表达（Sato 等 1998，Ducy 等 1999，Roce 等 2005）。RUNX2 介导的几种与 GPCR（G 蛋白偶联受体）信号传导相关的基因的转录调控，涉及成骨细胞前体增殖的控制（Teplyuk 等 2009）。RUNX2 通过刺激 IHH 基因（编码印度 Hedgehog）的转录，促进软骨细胞成熟（Takeda 等 2001，Yoshida 等 2004）。RUNX2 基因胚系功能丧失突变与成骨不全症（CCD）相关，这是一种常染色体骨骼发育障碍（综述于 Jaruga 等 2016）。RUNX2 的功能在成骨瘤中经常受到破坏（综述于 Mortus 等 2014）。维生素 D3 涉及 RUNX2:CBFB 复合物转录活性的调控（Underwood 等 2012）。RUNX2 表达受雌激素信号调控，RUNX2 涉及乳腺癌的发生和转移（综述于 Wysokinski 等 2014）。除了雌激素受体α（ESR1）和雌激素相关受体α（ERRA）（Kammerer 等 2013）外，RUNX2 转录还受 TWIST1（Yang, Yang 等 2011）、糖皮质激素受体（NR3C1）（Zhang 等 2012）、NKX3-2（BAPX1）（Tribioli 和 Lufkin 1999，Lengner 等 2005）、DLX5（Robledo 等 2002，Lee 等 2005）和 MSX2（Lee 等 2005）的调控。RUNX2 可通过直接抑制自身转录进行自调控（Drissi 等 2000）。几种 E3 泛素连接酶靶向 RUNX2 进行蛋白酶体降解：STUB1（CHIP）（Li 等 2008）、SMURF1（Zhao 等 2003，Yang 等 2014）、WWP1（Jones 等 2006）和 SKP2（Thacker 等 2016）。除了形成 RUNX2:CBFB 异二聚体外，RUNX2 的转录活性还通过与多种其他转录因子结合进行调控，例如 SOX9（Zhou 等 2006，TWIST1（Bialek 等 2004）和 RB1（Thomas 等 2001））。RUNX2 调控与正常发育和乳腺癌细胞骨转移过程中细胞迁移相关的几种基因表达。RUNX2 刺激 ITGA5 基因（编码整合素α5）和 ITGBL1 基因（编码整合素β类似蛋白 1）的转录（Li 等 2016）。RUNX2 介导的 MMP13 基因（编码基质金属蛋白酶 13，即胶原酶 3）的转录受 AKT 介导的 RUNX2 磷酸化刺激（Pande 等 2013）。RUNX2 涉及对 AKT 信号传导的正向调控，通过刺激 AKT 激活 TORC2 复合物的组分 MTOR 和 RICTOR 的表达，这可能有助于乳腺癌细胞的生存（Tandon 等 2014）。RUNX2 抑制 CDKN1A 转录，从而防止 CDKN1A 诱导的细胞周期停滞。CDK4 在响应高葡萄糖时磷酸化 RUNX2，增强 RUNX2 对 CDKN1A 基因的抑制作用（Pierce 等 2012）。在小鼠中，Runx2 介导的 Cdkn1a 抑制可能有助于急性髓系白血病的发育（Kuo 等 2009）。RUNX2 可刺激 LGALS3 基因（编码半乳糖凝集素 3）的转录（Vladimirova 等 2008，Zhang 等 2009）。半乳糖凝集素 3 在髓系前体细胞中表达，其水平在成熟过程中增加（Le Marer 2000）。关于 RUNX2 功能的综述请参见 Long 2012 和 Ito 等 2015。
英文描述
Transcriptional regulation by RUNX2 RUNX2 (CBFA1 or AML3) transcription factor, similar to other RUNX family members, RUNX1 and RUNX3, can function in complex with CBFB (CBF-beta) (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002). RUNX2 mainly regulates transcription of genes involved in skeletal development (reviewed in Karsenty 2008). RUNX2 is involved in development of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. RUNX2 stimulates transcription of the BGLAP gene (Ducy and Karsenty 1995, Ducy et al. 1997), which encodes Osteocalcin, a bone-derived hormone which is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). RUNX2 directly controls the expression of most genes associated with osteoblast differentiation and function (Sato et al. 1998, Ducy et al. 1999, Roce et al. 2005). RUNX2-mediated transcriptional regulation of several genes involved in GPCR (G protein coupled receptor) signaling is implicated in the control of growth of osteoblast progenitors (Teplyuk et al. 2009). RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004). Germline loss-of-function mutations of the RUNX2 gene are associated with cleidocranial dysplasia syndrome (CCD), an autosomal skeletal disorder (reviewed in Jaruga et al. 2016). The function of RUNX2 is frequently disrupted in osteosarcoma (reviewed in Mortus et al. 2014). Vitamin D3 is implicated in regulation of transcriptional activity of the RUNX2:CBFB complex (Underwood et al. 2012).RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA) (Kammerer et al. 2013), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1) (Zhang et al. 2012), NKX3-2 (BAPX1) (Tribioli and Lufkin 1999, Lengner et al. 2005), DLX5 (Robledo et al. 2002, Lee et al. 2005) and MSX2 (Lee et al. 2005). RUNX2 can autoregulate, by directly inhibiting its own transcription (Drissi et al. 2000). Several E3 ubiquitin ligases target RUNX2 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). Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 (Bialek et al. 2004) and RB1 (Thomas et al. 2001).RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 (Li et al. 2016) and the ITGBL1 gene, encoding Integrin beta like protein 1 (Li et al. 2015). RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2 (Pande et al. 2013). RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells (Tandon et al. 2014).RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells (Pierce et al. 2012). In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML) (Kuo et al. 2009). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3 (Vladimirova et al. 2008, Zhang et al. 2009). Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015.
所含基因
18 个基因