Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B.
Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B.
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发表时间：
1996-02
期刊：
影响因子：
11.2
通讯作者：
James G. Herman;J. Jen;A. Merlo;S. Baylin
中科院分区：
文献类型：
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作者：
James G. Herman;J. Jen;A. Merlo;S. Baylin
最近发现的周期蛋白依赖性激酶抑制剂p15INK4B定位于人类肿瘤中经常缺失的染色体9p21上的一个区域。先前的证据指出，一个相关基因p16INK4A是这种缺失的主要目标。我们报道，在胶质瘤和白血病中，p15基因的失活通常与启动子区域超甲基化有关，涉及5'-CpG岛的多个位点。在一些胶质瘤和所有原发性白血病中，该事件发生时邻近基因p16INK4A没有改变。在其他肿瘤中，包括肺癌、头颈癌、乳腺癌、前列腺癌和结肠癌，p15INK4B的失活很少发生，而且只伴随p16的失活。p15INK4B的异常甲基化与该基因的转录缺失有关。用去甲基化剂5-aza-2'-脱氧胞苷处理导致p15mrna的重新表达。在选定的白血病细胞系中，p15失活与已知的对转化生长因子- β的生长抑制作用的抗性相关。这些结果表明，p15INK4B在白血病和胶质瘤中选择性失活，似乎构成了这些肿瘤中重要的肿瘤抑制基因丢失。
The recently identified cyclin-dependent kinase inhibitor p15INK4B is localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16INK4A, as the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivated in association with promoter region hypermethylation involving multiple sites in a 5'-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16INK4A. In other tumors, including lung, head and neck, breast, prostate, and colon cancer, inactivation of p15INK4B occurs only rarely and only with concomitant inactivation of p16. Aberrant methylation of p15INK4B is associated with transcriptional loss of this gene. Treatment with the demethylating agent 5-aza-2'-deoxycytidine leads to re-expression of p15 mRNA. In selected leukemia cell lines, p15 inactivation correlates with known resistance to the growth-suppressive effects of transforming growth factor-beta. These results suggest that p15INK4B is inactivated selectively in leukemias and gliomas and seems to constitute an important tumor suppressor gene loss in these neoplasms.