Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling.
Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling.
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DOI：
10.1002/dvdy.23858
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发表时间：
2012-11
影响因子：
2.5
通讯作者：
D'Souza, Rena N.
中科院分区：
文献类型：
--
作者：
Lu, Yongbo;Li, Yucheng;Cavender, Adriana C.;Wang, Suzhen;Mansukhani, Alka;D'Souza, Rena N.
由于Runx2突变导致单倍性缺失，在患有锁骨颅骨发育不良的患者中经常观察到多生牙。然而，基本的分子机制是不明确的。在这项研究中，我们评估了Runx2和其功能拮抗剂Twist 1在调节成纤维细胞生长因子（FGF）信号转导中的作用，使用体外生物化学方法。我们发现Twist 1刺激Fgfr 2和Fgf 10在间充质细胞系中的表达，并且它与普遍表达的E12（连同由E2A基因编码的E47）形成异二聚体，并且在牙齿间充质衍生的细胞系中上调Fgfr 2和Fgf 10启动子活性。我们进一步证明了Twist 1的bHLH结构域是其与E12协同激活Fgfr 2启动子所必需的，并且E12的结合通过防止Twist 1经历溶酶体降解来稳定Twist 1。Runx2对Fgfr 2和Fgf 10启动子活性无明显影响，但能抑制Twist 1对Fgfr 2启动子的激活作用。这些发现表明Runx2单倍不足可能导致过度未结合的Twist1，其可以自由结合E12并增强FGF信号传导，从而促进额外牙齿的形成。
Supernumerary teeth are often observed in patients suffering from cleidocranial dysplasia due to a mutation in Runx2 that results in haploinsufficiencty. However, the underlying molecular mechanisms are poorly defined. In this study, we assessed the roles of Runx2 and its functional antagonist Twist1 in regulating fibroblast growth factor (FGF) signaling using in vitro biochemical approaches. We showed that Twist1 stimulated Fgfr2 and Fgf10 expression in a mesenchymal cell line and that it formed heterodimers with ubiquitously expressed E12 (together with E47 encoded by E2A gene) and upregulated Fgfr2 and Fgf10 promoter activities in a dental mesenchyme-derived cell line. We further demonstrated that the bHLH domain of Twist1 was essential for its synergistic activation of Fgfr2 promoter with E12 and that the binding of E12 stabilized Twist1 by preventing it from undergoing lysosomal degradation. Although Runx2 had no apparent effects on Fgfr2 and Fgf10 promoter activities, it inhibited the stimulatory activity of Twist1 on Fgfr2 promoter. These findings suggest that Runx2 haploinsufficiency might result in excessive unbound Twist1 that can freely bind to E12 and enhance FGF signaling, thereby promoting the formation of extra teeth.
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DOI：
10.1073/pnas.0910086106
发表时间：
2009-12-29
影响因子：
11.1
作者：
Charles, Cyril;Lazzari, Vincent;Viriot, Laurent
通讯作者：
Viriot, Laurent
影响因子：
7.6
作者：
Galler, K. M.;Yasue, A.;D'Souza, R. N.
通讯作者：
D'Souza, R. N.
影响因子：
3.3
作者：
JENSEN, BL;KREIBORG, S
通讯作者：
KREIBORG, S
影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
Osf2/Cbfa1：成骨细胞分化的转录激活因子
影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G