SUPPRESSION OF HUMAN COLORECTAL-CARCINOMA CELL-GROWTH BY WILD-TYPE-P53
SUPPRESSION OF HUMAN COLORECTAL-CARCINOMA CELL-GROWTH BY WILD-TYPE-P53
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DOI：
10.1126/science.2144057
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发表时间：
1990-08-24
期刊：
影响因子：
56.9
通讯作者：
VOGELSTEIN, B
中科院分区：
文献类型：
--
作者：
BAKER, SJ;MARKOWITZ, S;VOGELSTEIN, B
p53基因突变通常发生在结直肠癌中，并且野生型p53等位基因常常伴随缺失。这些结果表明，野生型基因可能作为大肠癌细胞生长的抑制剂。为了验证这一假设，将野生型或突变型人p53基因转染到人结肠直肠癌细胞系中。用野生型基因转染的细胞形成集落的效率比用突变型p53基因转染的细胞低五到十倍。在野生型基因转染后确实形成的那些集落中，发现p53序列被删除或重排，或两者兼而有之，并且没有观察到外源性p53信使RNA表达。与此相反，野生型基因的转染没有明显的影响，从良性结直肠肿瘤，只有野生型p53等位基因的上皮细胞的生长。免疫细胞化学技术表明，表达野生型基因的癌细胞没有通过细胞周期的进展，证明了他们未能将胸苷到DNA。这些研究表明，野生型基因可以特异性地抑制体外人结肠直肠癌细胞的生长，并且导致p53基因产物中单个保守氨基酸取代的体内衍生突变消除了这种抑制能力。
Mutations of the p53 gene occur commonly in colorectal carcinomas and the wild-type p53 allele is often concomitantly deleted. These findings suggest that the wild-type gene may act as a suppressor of colorectal carcinoma cell growth. To test this hypothesis, wild-type or mutant human p53 genes were transfected into human colorectal carcinoma cell lines. Cells transfected with the wild-type gene formed colonies five- to tenfold less efficiently than those transfected with a mutant p53 gene. In those colonies that did form after wild-type gene transfection, the p53 sequences were found to be deleted or rearranged, or both, and no exogenous p53 messenger RNA expression was observed. In contrast, transfection with the wild-type gene had no apparent effect on the growth of epithelial cells derived from a benign colorectal tumor that had only wild-type p53 alleles. Immunocytochemical techniques demonstrated that carcinoma cells expressing the wild-type gene did not progress through the cell cycle, as evidenced by their failure to incorporate thymidine into DNA. These studies show that the wild-type gene can specifically suppress the growth of human colorectal carcinoma cells in vitro and that an in vivo-derived mutation resulting in a single conservative amino acid substitution in the p53 gene product abrogates this suppressive ability.