Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
PLoS One. 2011;6(7):e22096. doi: 10.1371/journal.pone.0022096. Epub 2011 Jul 8.
Inactivation of the p53 pathway that controls cell cycle progression, apoptosis and senescence, has been proposed to occur in virtually all human tumors and p53 is the protein most frequently mutated in human cancer. However, the mutational status of p53 in melanoma is still controversial; to clarify this notion we analysed the largest series of melanoma samples reported to date.
METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical analysis of more than 180 melanoma specimens demonstrated that high levels of p53 are expressed in the vast majority of cases. Subsequent sequencing of the p53 exons 5-8, however, revealed only in one case the presence of a mutation. Nevertheless, by means of two different p53 reporter constructs we demonstrate transcriptional inactivity of wild type p53 in 6 out of 10 melanoma cell lines; the 4 other p53 wild type melanoma cell lines exhibit p53 reporter gene activity, which can be blocked by shRNA knock down of p53.
CONCLUSIONS/SIGNIFICANCE: In melanomas expressing high levels of wild type p53 this tumor suppressor is frequently inactivated at transcriptional level.
控制细胞周期进程、细胞凋亡和衰老的 p53 通路失活，几乎存在于所有人类肿瘤中，p53 是人类癌症中最常发生突变的蛋白。然而，黑色素瘤中 p53 的突变状态仍存在争议；为了阐明这一观点，我们分析了迄今为止报道的最大系列黑色素瘤样本。
方法/主要发现： 对 180 多个黑色素瘤标本进行免疫组化分析表明，绝大多数病例中 p53 表达水平较高。然而，随后对 p53 外显子 5-8 的测序仅在一例中发现存在突变。尽管如此，通过两种不同的 p53 报告基因构建体，我们证明了 10 个黑色素瘤细胞系中有 6 个存在野生型 p53 的转录失活；另外 4 个野生型 p53 黑色素瘤细胞系表现出 p53 报告基因活性，该活性可通过 shRNA 敲低 p53 来阻断。
结论/意义： 在表达高水平野生型 p53 的黑色素瘤中，这种肿瘤抑制因子经常在转录水平失活。
