THE HUMAN PAPILLOMA-VIRUS 16E6 GENE SENSITIZES HUMAN MAMMARY EPITHELIAL-CELLS TO APOPTOSIS INDUCED BY DNA-DAMAGE
THE HUMAN PAPILLOMA-VIRUS 16E6 GENE SENSITIZES HUMAN MAMMARY EPITHELIAL-CELLS TO APOPTOSIS INDUCED BY DNA-DAMAGE
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DOI：
10.1073/pnas.92.17.7829
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发表时间：
1995-08-15
影响因子：
11.1
通讯作者：
SAGER, R
中科院分区：
文献类型：
--
作者：
XU, C;MEIKRANTZ, W;SAGER, R
程序性细胞死亡（凋亡）是一种正常的生理过程，原则上可以操纵它在癌症治疗中发挥重要作用。由于p53突变或缺失在大多数癌症中很常见，因此p53表达在对DNA损伤剂的凋亡反应中的关键重要性一直受到强调。因此，一个重要的策略是找到在野生型p53不存在的情况下诱导凋亡的方法。在本文中，我们比较了正常人乳腺上皮细胞的凋亡，在细胞永生化与人乳头状瘤病毒（HPV），乳腺癌细胞系表达野生型p53，突变型p53，或没有p53蛋白。用丝裂霉素C（MMC）和星形孢菌素（SSP）诱导细胞凋亡。SSP对正常细胞和HPV转染细胞的作用强于肿瘤细胞。暴露于MMC后，表达野生型p53的细胞发生了广泛的凋亡，而携带突变型p53的细胞反应较弱。p53蛋白缺失的原代乳腺癌细胞系对MMC耐药。与此相反，两个HPV永生化细胞系，其中p53蛋白被破坏的E6调节的泛素化是高度敏感的MMC诱导的凋亡。MMC处理后，HPV永生化细胞中p53 mRNA和蛋白均未诱导表达，但在野生型p53细胞中，MMC升高了p53蛋白。重要的是，MMC诱导HPV永生化细胞中p21 mRNA而不是p21蛋白的表达。因此，HPV 16 E6可以通过p53和p21非依赖性途径使乳腺上皮细胞对MMC诱导的凋亡敏感。我们认为HPV 16 E6蛋白不仅调节p53的泛素介导的降解，还调节p21和可能参与凋亡的其他蛋白的降解。
Programmed cell death (apoptosis) is a normal physiological process, which could in principle be manipulated to play an important role in cancer therapy. The key importance of p53 expression in the apoptotic response to DNA-damaging agents has been stressed because mutant or deleted p53 is so common in most kinds of cancer. An important strategy, therefore, is to find ways to induce apoptosis in the absence of wild-type p53. In this paper, we compare apoptosis in normal human mammary epithelial cells, in cells immortalized with human papilloma virus (HPV), and in mammary carcinoma cell lines expressing wild-type p53, mutant p53, or no p53 protein. Apoptosis was induced with mitomycin C (MMC), a DNA cross-linking and damaging agent, or with staurosporine (SSP), a protein kinase inhibitor, The normal and HPV-transfected cells responded more strongly to SSP than did the tumor cells. After exposure to MMC, cells expressing wild-type p53 underwent extensive apoptosis, whereas cells carrying mutated p53 responded weakly. Primary breast cancer cell lines null for p53 protein were resistant to MMC. In contrast, two HPV immortalized cell lines in which p53 protein was destroyed by E6-modulated ubiquitinylation were highly sensitive to apoptosis induced by MMC. Neither p53 mRNA nor protein was induced in the HPV immortalized cells after MMC treatment, although p53 protein was elevated by MMC in cells with wild-type p53. Importantly, MMC induced p21 mRNA but not p21 protein expression in the HPV immortalized cells. Thus, HPV 16E6 can sensitize mammary epithelial cells to MMC-induced apoptosis via a p53- and p21-independent pathway. We propose that the HPV 16E6 protein modulates ubiquitin-mediated degradation not only of p53 but also of p21 and perhaps other proteins involved in apoptosis.