activated ras alters lens and corneal development through induction of distinct downstream targets通过感应ras激活改变镜头和角膜发展不同的下游目标.pdfVIP

Burgess et al. BMC Developmental Biology 2010, 10:13 /1471-213X/10/13 RESEARCH ARTICLE Open Access Activated Ras alters lens and corneal development through induction of distinct downstream targets 1 1 1 1 1 2 3 Daniel Burgess , Yan Zhang , Ed Siefker , Ryan Vaca , Murali R Kuracha , Lixing Reneker , Paul A Overbeek , Venkatesh Govindarajan 1* Abstract Background: 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. Results: 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 upregulate