Melanoma cells can tolerate high levels of transcriptionally active endogenous p53 but are sensitive to retrovirus-transduced p53
Melanoma cells can tolerate high levels of transcriptionally active endogenous p53 but are sensitive to retrovirus-transduced p53
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DOI：
10.1038/sj.onc.1206741
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发表时间：
2003-07-31
期刊：
影响因子：
8
通讯作者：
Gudkov, AV
中科院分区：
文献类型：
--
作者：
Kichina, JV;Rauth, S;Gudkov, AV
恶性黑色素瘤通常以野生型P53水平升高为特征，这表明P53功能可能被一种不同于P53突变的机制抑制。我们分析了七个人黑色素瘤细胞系中P53信号通路的功能，其中包括一个P53缺陷株，两个突变型P53株和四个表达野生型P53的株。只有野生型P53的特征是内源性p21水平升高，P53反应报告高活性，以及对遗传毒性应激反应中P53的积累，这些都是功能性P53的共同特征。野生型P53的存在与p14(ARF)和p16表达的缺失或缺失有关。P33(ING1b)和p24(ING1c)是Ing1基因座的两个主要产物，也是P53的共同调节因子，在所有细胞系中均有表达，但ING1亚型的异位表达对细胞增殖无影响。所有的细胞株都保留了APAF-1的表达，并且除一株外，所有株系对逆转录病毒转导的p53的异位表达仍然敏感。我们的数据表明，无论黑色素瘤中P53的水平是否异常高，他们的P53仍然能够反式激活其靶标，如果高度过度表达，则能够抑制生长。因此，恶性黑色素瘤中的P53通路可以考虑用于药物靶向和抗癌基因治疗。
Malignant melanomas are frequently characterized by elevated levels of wild-type p53, suggesting that p53 function could be suppressed by a mechanism different from p53 mutation. We analysed the functionality of the p53-signaling pathway in a panel of seven human melanoma cell lines consisting of one p53-deficient line, two lines with mutant p53, and four lines expressing wildtype p53. Only lines with wild-type p53 were characterized by elevated levels of endogenous p21, high activity of p53-responsive reporters and accumulation of p53 in response to genotoxic stress, common properties of functional p53. The presence of wild-type p53 was associated with depletion or loss of p14(ARF) and p16 expression. The levels of p33(ING1b) and p24(ING1c), two major products of Ing1 locus and putative coregulators of p53, were elevated in all cell lines tested; however, ectopic expression of either ING1 isoform had no effect on cell proliferation. All lines retained expression of Apaf-1, and all but one remained sensitive to ectopic expression of retrovirus-transduced p53. Our data indicate that regardless of abnormally high levels of p53 in melanomas, their p53 remains competent in transactivation of its targets, and, if highly overexpressed, capable of growth inhibition. Hence, the p53 pathway in malignant melanomas can be considered for pharmacological targeting and anticancer gene therapy.