Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.
Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.
复制标题
DOI：
--
复制
发表时间：
1996-12
期刊：
影响因子：
--
通讯作者：
D. Brash;A. Ziegler;A. Jonason;J. Simon;S. Kunala;D. Leffell
中科院分区：
文献类型：
--
作者：
D. Brash;A. Ziegler;A. Jonason;J. Simon;S. Kunala;D. Leffell
阳光是一种致癌物质，每个人都暴露在其中。流行病学表明，大多数致癌的阳光照射发生在肿瘤出现之前的几十年。一些早期的事件已经通过寻找具有紫外线（UV）特异性突变的基因来确定。来自新英格兰患者的超过90%的鳞状细胞癌和超过50%的基底细胞癌在p53肿瘤抑制基因中含有UV样突变。从突变模式，可以得出结论，致癌的DNA病变是嘧啶-胞嘧啶光产物所造成的紫外线B部分的阳光。p53基因的特定密码子是最敏感的，显然是因为在特定位点的DNA修复较慢。阳光具有足够的致突变性，常常使两个p53等位基因突变。这些突变也发现在癌前鳞状细胞癌，光化性角化病，这意味着早期的作用。p53在正常皮肤中的功能通过观察到小鼠皮肤中的p53失活减少了晒伤细胞、由UV过度照射产生的凋亡角质形成细胞的出现来指示。因此，皮肤似乎拥有一种依赖于p53的“细胞校对”反应，以应对癌前细胞自我破坏的DNA损伤。如果这种反应在单个细胞中被先前的p53突变降低，那么晒伤可以随后选择p53突变细胞的克隆扩增而成为光化性角化病。阳光似乎有两种作用：作为肿瘤引发剂和肿瘤促进剂。
Sunlight is a carcinogen to which everyone is exposed. Epidemiology indicates that most carcinogenic sunlight exposure takes place several decades before the tumor arises. Some of the early events have been identified by searching for genes having ultraviolet (UV)-specific mutations. Over 90% of squamous cell carcinomas and more than 50% of basal cell carcinomas from New England patients contain UV-like mutations in the p53 tumor suppressor gene. From the mutation pattern, it can be concluded that the carcinogenic DNA lesions were pyrimidine-cytosine photoproducts caused by the UVB portion of sunlight. Particular codons of the p53 gene are most susceptible, apparently because of slower DNA repair at specific sites. Sunlight is sufficiently mutagenic often to mutate both p53 alleles. These mutations are also found in the precancer for squamous cell carcinoma, actinic keratosis, implying an early role. The function of p53 in normal skin is indicated by the observation that inactivating p53 in mouse skin reduces the appearance of sunburn cells, apoptotic keratinocytes generated by UV overexposure. Skin thus appears to possess a p53-dependent "cellular proofreading" response to DNA damage in which precancerous cells self-destruct. If this response is reduced in a single cell by a prior p53 mutation, sunburn can thereafter select for clonal expansion of the p53-mutated cell into an actinic keratosis. Sunlight appears to act twice: as tumor initiator and as tumor promoter.