Activated Ras alters lens and corneal development through induction of distinct downstream targets.
Activated Ras alters lens and corneal development through induction of distinct downstream targets.
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DOI：
10.1186/1471-213x-10-13
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发表时间：
2010-01-27
影响因子：
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通讯作者：
Govindarajan V
中科院分区：
文献类型：
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作者：
Burgess D;Zhang Y;Siefker E;Vaca R;Kuracha MR;Reneker L;Overbeek PA;Govindarajan V
哺乳动物Ras基因调节多种细胞过程，包括增殖和分化，并且在人类癌症中经常突变。响应Ras激活的肿瘤发展在不同组织之间变化，并且这些变化的分子基础知之甚少。小鼠的透镜和角膜具有共同的胚胎起源，并且产生于表面外胚层的相邻区域。成纤维细胞生长因子（FGF）信号通路的激活诱导角膜上皮细胞增殖和透镜上皮细胞退出细胞周期。调节这两种相关组织的差异反应的分子机制尚未确定。我们已经产生了转基因小鼠，在他们的晶状体和角膜中表达组成型活性版本的人H-Ras。Ras转基因晶状体和角膜上皮细胞增殖增加，同时细胞周期蛋白D1和D2表达增加。这种增殖的初始增加在角膜中持续，但在透镜上皮细胞中不持续。巧合的是，cdk抑制剂p27 Kip 1和p57 Kip 2在Ras转基因晶状体中上调，但在角膜中不上调。磷酸化Erk 1和Erk 2水平在透镜中升高，但在角膜中不升高，而Ras-Raf-Erk信号的负调节因子Spry 1和Spry 2在角膜中的上调程度高于透镜上皮细胞。透镜和角膜分化程序都对Ras激活敏感。Ras转基因胚的透镜窝结构发生了明显的变化。Ras激活，虽然足以上调Prox 1，一个转录因子的细胞周期退出和启动纤维分化的关键，是不足以诱导终末纤维分化。角蛋白12的表达，角膜上皮分化的标志物，在Ras转基因角膜减少。总的来说，这些结果表明Ras激活a）在透镜和角膜中诱导不同的下游靶点组，导致不同的细胞反应，和B）足以启动但不完成透镜纤维分化。
Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF) signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas. Ras transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases in cyclin D1 and D2 expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitors p27Kip1 and p57Kip2 were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea and Spry 1 and Spry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation of Prox1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas. Collectively, these results suggest that Ras activation a) induces distinct sets of downstream targets in the lens and cornea resulting in distinct cellular responses and b) is sufficient for initiation but not completion of lens fiber differentiation.