Role of the INK4a locus in tumor suppression and cell mortality
Role of the INK4a locus in tumor suppression and cell mortality
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DOI：
10.1016/s0092-8674(00)81079-x
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发表时间：
1996-04-05
期刊：
影响因子：
64.5
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Serrano, M;Lee, HW;DePinho, RA
细胞周期抑制因子p16(INK4a)在许多人类肿瘤以及遗传性黑色素瘤和胰腺癌家族中失活。肿瘤相关的INK4a基因改变也可能影响编码p19的重叠基因(ARF)和邻近的编码p15的基因(INK4b)，这两个基因都是细胞增殖的负面调节因子。我们报告了携带INK4a基因定点缺失的小鼠的表型，该基因缺失同时消除了p-16(INK4a)和p19(ARF)。这些小鼠是存活的，但在很小的时候就会患上自发性肿瘤，并且对致癌治疗高度敏感。Ink4a缺失的原代成纤维细胞增殖迅速，集落形成率高。与正常细胞相比，将活化的Ha-ras基因导入INK4a缺失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。
The cell cycle inhibitor p16(INK4a) 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 p19(ARF) and the adjacent gene encoding p15(INK4b), both negative regulators of cell proliferation. We report the phenotype of mice carrying a targeted deletion of the INK4a locus that eliminates both p-16(INK4a) and p19(ARF). 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.