Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho R A
Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, 11724 USA.
Cell. 1996 Apr 5;85(1):27-37. doi: 10.1016/s0092-8674(00)81079-x.
The cell cycle inhibitor p16INK4a is inactivated in many human tumors and in families with hereditary melanoma and pancreatic cancer. Tumor-associated alterations in the INK4a locus may also affect the overlapping gene encoding p19ARF and the adjacent gene encoding p15I1NK4b, both negative regulators of cell proliferation. We report the phenotype of mice carrying a targeted deletion of the INK4a locus that eliminates both p16INK4a and p19ARF. The mice are viable but develop spontaneous tumors at an early age and are highly sensitive to carcinogenic treatments. INK4a-deficient primary fibroblasts proliferate rapidly and have a high colony-formation efficiency. In contrast with normal cells, the introduction of activated Ha-ras into INK4a-deficient fibroblasts can result in neoplastic transformation. These findings directly demonstrate that the INK4a locus functions to suppress neoplastic growth.
细胞周期抑制剂p16INK4a在许多人类肿瘤以及遗传性黑素瘤和胰腺癌家族中失活。INK4a基因座中与肿瘤相关的改变也可能影响编码p19ARF的重叠基因和编码p15I1NK4b的相邻基因，二者均为细胞增殖的负调节因子。我们报告了携带INK4a基因座靶向缺失的小鼠的表型，该缺失消除了p16INK4a和p19ARF。这些小鼠是存活的，但在幼年时会自发发生肿瘤，并且对致癌处理高度敏感。INK4a缺陷的原代成纤维细胞增殖迅速，且具有较高的集落形成效率。与正常细胞相反，将活化的Ha-ras导入INK4a缺陷的成纤维细胞可导致肿瘤转化。这些发现直接证明INK4a基因座具有抑制肿瘤生长的功能。
