P53 GENE IN HUMAN NEOPLASIA

我们最近的实验证明，p53基因是一种 人类肿瘤生长的抑制基因和该基因在一个大的 人类癌症的数量。这些癌症包括脑癌、结肠癌、 肺、乳腺、卵巢、骨骼和膀胱；实际上，P53是最常见的 在人类肿瘤中尚未发现突变基因，几乎在 美国每年发生的癌症总数的一半。 因此，了解p53基因在人类肿瘤发生中的作用 成为一个极其重要的研究目标。 这项建议旨在继续我们对P53的调查 通过各种方法，包括(I)临床研究，以确定 人类肿瘤发生过程中P53基因突变的时序 以及遗传性基因突变在易感家系中的流行率 癌症的发展；(Ii)生理学研究，以检查 野生型和突变型P53的表达对细胞生长和细胞周期调控的影响 含有内源性P53基因突变的癌细胞； 研究，以发现在体内调节P53作用的基因，在这两种情况下 哺乳动物和低等真核生物环境；以及(Iv)生化研究， 体外鉴定P53结合的DNA序列和细胞蛋白 在活体内。这些方法中的每一种都有可能阐明 P53功能的特定方面。它们结合在一起，应该会带来新的 对肿瘤抑制基因原型的生物学洞察力， 对不同形式的人类肿瘤的影响。

Our recent experiments have demonstrated that the p53 gene is a suppressor of human tumor growth and that this gene is mutated in a large number of human cancers. These cancers include those of the brain, colon, lung, breast, ovary, bone and bladder; indeed, p53 is the most commonly mutated gene yet identified in human tumors, genetically altered in nearly half the total cancers that occur in the United States annually. Understanding the role of the p53 gene in human tumorigenesis therefore has become a critically important research goal. This proposal is designed to continue our investigations on p53 through a variety of approaches, including (i) clinical studies, to define the timing of p53 gene mutations during the course of human tumorigenesis, and the prevalence of inherited gene mutations in families predisposed to cancer development; (ii) physiologic studies, to examine the effects of wild-type and mutant p53 expression on the growth and cell cycle control of cancer cells containing endogenous p53 gene mutations; (iii) genetic studies, to discover genes that modulate p53 action in vivo, in both mammalian and lower eukaryotic environments; and (iv) biochemical studies, to identify DNA sequences and cellular proteins to which p53 binds in vitro and in vivo. Each of these approaches has the potential to illuminate specific aspects of p53 function. In combination, they should lead to new insights into the biology of a prototype tumor suppressor gene, with implications for diverse forms of human neoplasia.