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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells.
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Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells.

机译：UVB辐射在小鼠皮肤癌变中的早期p53改变：肿瘤前表皮细胞簇中突变p53蛋白的免疫组织化学检测。

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High levels of the p53 protein are immunohistochemically detectable in a majority of human nonmelanoma skin cancers and UVB-induced murine skin tumors. These increased protein levels are often associated with mutations in the conserved domains of the p53 gene. To investigate the timing of the p53 alterations in the process of UVB carcinogenesis, we used a well defined murine model (SKH:HR1 hairless mice) in which the time that tumors appear is predictable from the UVB exposures. The mice were subjected to a series of daily UVB exposures, either for 17 days or for 30 days, which would cause skin tumors to appear around 80 or 30 weeks, respectively. In the epidermis of these mice, we detected clusters of cells showing a strong immunostaining of the p53 protein, as measured with the CM-5 polyclonal antiserum. This cannot be explained by transient accumulation of the normal p53 protein as a physiological response to UVB-induced DNA damage. In single exposure experiments the observed transient CM-5 immunoreactivity lasted for only 3 days and was not clustered, whereas these clusters were still detectable as long as 56 days after 17 days of UVB exposure. In addition, approximately 70% of these patches reacted with the mutant-specific monoclonal antibody PAb240, whereas transiently induced p53-positive cells did not. In line with indicative human data, these experimental results in the hairless mouse model unambiguously demonstrate that constitutive p53 alterations are causally related to chronic UVB exposure and that they are a very early event in the induction of skin cancer by UVB radiation.
机译：在大多数人类非黑素瘤皮肤癌和UVB诱导的鼠类皮肤肿瘤中，免疫组化可检测到高水平的p53蛋白。这些增加的蛋白质水平通常与p53基因保守域中的突变有关。为了研究UVB致癌过程中p53改变的时机，我们使用了定义明确的小鼠模型（SKH：HR1无毛小鼠），其中从UVB暴露可以预测出现肿瘤的时间。每天对小鼠进行一系列的UVB暴露，分别为17天或30天，这将导致皮肤肿瘤分别在80或30周左右出现。在这些小鼠的表皮中，我们检测到细胞簇，这些细胞簇显示出p53蛋白的强免疫染色，如使用CM-5多克隆抗血清所测。无法通过正常p53蛋白的短暂积累作为对UVB诱导的DNA损伤的生理反应来解释。在单次暴露实验中，观察到的瞬时CM-5免疫反应仅持续了3天，并且没有聚类，而在UVB暴露17天后的56天内仍可检测到这些簇。此外，这些贴片中约有70％与突变型特异性单克隆抗体PAb240反应，而瞬时诱导的p53阳性细胞则没有。与指示性人类数据一致，这些无毛小鼠模型中的实验结果明确表明，p53组成性改变与慢性UVB暴露有因果关系，它们是通过UVB辐射诱发皮肤癌的非常早期的事件。

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