Transformation of mortal human fibroblasts and activation of a growth inhibitory pathway by the bovine papillomavirus E5 oncoprotein.

L M Petti, F A Ray
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Abstract

The 44-amino acid bovine papillomavirus E5 protein induces tumorigenic transformation of immortal rodent fibroblasts by binding to and activating the platelet-derived growth factor beta receptor (PDGFbetaR). Here E5 was expressed in mortal human diploid fibroblasts (HDFs), which lack the accumulated genetic changes that are present in immortal rodent cells. E5 induced focus formation and morphological transformation of HDFs without inducing anchorage independence or immortalization. Similar effects were observed with the v-sis and neu* oncogenes. E5-PDGFbetaR complexes were observed in the E5-expressing HDFs, as was constitutive PDGFbetaR activation, which was required for the transforming activity of E5. The E5 HDFs attained a higher saturation density than the control cells, expressing increased levels of hyperphosphorylated retinoblastoma protein at subconfluent densities. However, when these cells reached confluence, growth inhibition accompanied by dramatic down-regulation of the PDGFbetaR, and retinoblastoma protein was induced apparently by a factor secreted into the medium. This may represent a novel negative feedback mechanism controlling PDGFbetaR-induced proliferation and thereby protecting against complete transformation.

牛乳头瘤病毒E5癌蛋白对人死亡成纤维细胞的转化和生长抑制途径的激活。
44个氨基酸的牛乳头瘤病毒E5蛋白通过结合和激活血小板衍生生长因子β受体(PDGFbetaR)诱导不朽的啮齿动物成纤维细胞的致瘤性转化。E5在人类二倍体成纤维细胞(HDFs)中表达,这种细胞缺乏不朽的啮齿动物细胞中积累的遗传变化。E5诱导HDFs的焦点形成和形态转变,但不诱导锚定独立性或永生化。在v-sis和新*癌基因中观察到类似的效果。在表达E5的HDFs中观察到E5-PDGFbetaR复合物,这是组成型PDGFbetaR激活,这是E5转化活性所必需的。E5 HDFs比对照细胞获得更高的饱和密度,在亚融合密度下表达高磷酸化的视网膜母细胞瘤蛋白。然而,当这些细胞达到融合时,培养基中分泌的一种因子明显诱导了生长抑制,并伴有PDGFbetaR和视网膜母细胞瘤蛋白的显著下调。这可能代表了一种新的负反馈机制,控制pdgfbeta诱导的增殖,从而防止完全转化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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