REGULATION OF APOPTOSIS BY VIRAL TRANSFORMING PROTEINS

腺病毒编码两个参与转化的基因，E1a和E1B， 它们合作转化原代啮齿动物细胞。E1a基因产物 刺激细胞增殖但不能单独转化细胞 诱导细胞程序性死亡(细胞凋亡)。E1B的表达 基因或人类bcl2原癌基因，阻断E1a诱导的细胞死亡 高效率地进行转化。E1B基因编码两个 生产19K和55K蛋白质，这是独特的蛋白质。这两个都是 蛋白质通过阻断诱导的细胞死亡来促进E1a的转化。 此外，E1B 19K蛋白还能阻断肿瘤诱导的细胞凋亡 肿瘤坏死因子-a和抗Fas抗体。最近的结果来自 怀特博士的实验室已经表明，E1a蛋白诱导P53，而P53在 TURN可诱导细胞凋亡。E1B 55K蛋白直接结合P53和 可能会干扰其功能，就像SV40T抗原一样。这个 E1B-19K蛋白抑制P53的作用机制 未知。这项建议的目的是确定 细胞凋亡受P53调控。方法是定义E1a，c-myc， 肿瘤坏死因子-a和抗Fas抗体诱导p53和细胞凋亡以及E1B是如何 19K和bcl2蛋白可阻断这一作用。

Adenovirus encodes two genes involved in transformation, E1A and E1B, which cooperate to transform primary rodent cells.The E1A gene products stimulate cell proliferation but fail to transform cells alone due to the induction of programmed cell death (apoptosis). Expression of the E1B gene or the human bcl-2 proto-oncogene, blocks E1A-induced cell death to produce transformation with high efficiency. The E1B gene encodes two products the l9K and 55K proteins that are unique proteins. Both of these proteins enhance transformation by E1A by blocking induced cell death. Additionally, the E1B 19K protein can block apoptosis induced by tumor necrosis factor-a (TNF-a) and anti-Fas antibodies. Recent results from Dr. White's laboratory has shown that the E1A proteins induce p53 which in turn induces apoptosis. The E1B 55K protein directly binds p53 and presumably interferes with it's function like SV40 T antigen. The mechanism of action of the E1B l9K protein in suppression of p53 is unknown. The aim of this proposal is to ascertain the mechanism by which apoptosis by p53 is regulated. The approach is to define how E1A, c-myc, TNF-a, and anti-Fas antibodies induce p53 and apoptosis and how the E1B l9K and bcl-2 proteins block this effect.