Giampieri Silvia, García-Escudero Ramon, Green Judith, Storey Alan
Cancer Research UK, Skin Tumour Laboratory, 2 Newark Street, London E1 2AT, UK.
Oncogene. 2004 Jul 29;23(34):5864-70. doi: 10.1038/sj.onc.1207711.
DNA damage, such as that elicited by UV-B, can induce either a cell cycle arrest or apoptosis that can be signalled by the p53 protein through the activation of a number of downstream cellular target genes. In contrast to oncogenic anogenital human papillomaviruses (HPVs), which mediate proteolytic degradation of p53, the E6 protein of cutaneous HPVs, such as HPV 77, do not promote p53 degradation. We have previously shown, however, that expression of HPV 77 E6 can effectively block UV-induced apoptosis in cells that have UV-activated p53. Here, we report that expression of the E6 protein from the cutaneous HPV 77 attenuates the UV-induced transactivation of p53-regulated proapoptotic genes Fas, PUMAbeta, Apaf-1, PIG3. This inhibition of p53-activation of proapoptotic genes by HPV77 E6 is exerted selectively, as the increased expression of p53 target genes involved in cell cycle arrest or regulatory functions regulation, such as p21 and Hdm2, is unaffected. Our data suggest that HPV 77 E6 may play an important role in specifically deregulating p53-dependent transactivation of proapoptotic genes upon UV-B irradiation.
DNA损伤，如由UV-B引发的损伤，可诱导细胞周期停滞或凋亡，这可由p53蛋白通过激活许多下游细胞靶基因发出信号。与介导p53蛋白水解降解的致癌性肛门生殖器人乳头瘤病毒（HPV）不同，皮肤HPV（如HPV 77）的E6蛋白不会促进p53降解。然而，我们之前已经表明，HPV 77 E6的表达可以有效阻断紫外线激活p53的细胞中的紫外线诱导的凋亡。在此，我们报告皮肤HPV 77的E6蛋白表达减弱了紫外线诱导的p53调节的促凋亡基因Fas、PUMAbeta、Apaf-1、PIG3的反式激活。HPV77 E6对p53激活促凋亡基因的这种抑制作用具有选择性，因为参与细胞周期停滞或调节功能调节的p53靶基因（如p21和Hdm2）的表达增加不受影响。我们的数据表明，HPV 77 E6可能在紫外线B照射后特异性解除p53依赖性促凋亡基因的反式激活中发挥重要作用。
