Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells
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DOI：
10.1038/sj.onc.1209158
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发表时间：
2006-02-23
期刊：
影响因子：
8
通讯作者：
Ikeda, MA
中科院分区：
文献类型：
--
作者：
Ichwan, SJA;Yamada, S;Ikeda, MA
为了研究p53磷酸化的失调是否赋予肿瘤对p53的抗性，我们分析了野生型p53对携带各种p53突变的口腔鳞状细胞癌（SCC）细胞系的影响。外源性p53的引入既不诱导细胞凋亡，也不抑制缺乏任何可检测的p53的HSC-3细胞和表达突变型p53 R248 Q蛋白的HSC-4细胞的集落形成。一致的是，外源性p53并没有诱导这些p53耐药细胞中的促凋亡p53靶基因。我们发现，外源性p53的丝氨酸46（Ser 46）的磷酸化严重受损的HSC-3，但不是HSC-4细胞。模拟丝氨酸46磷酸化的突变体（p53 S46 D）增强了促凋亡Noxa启动子的活性，并克服了HSC-3细胞对p53介导的凋亡和生长抑制的抗性。相反，丝氨酸46磷酸化缺陷突变体（p53 S46 A）未能抑制p53敏感的HSC-2细胞的生长。与HSC-3细胞相反，p53 S46 D对HSC-4细胞没有影响，并且通过siRNA抑制内源性p53 R248 Q恢复了HSC-4细胞中p53介导的凋亡，表明p53 R248 Q蛋白对野生型p53功能的显性负效应。这些结果表明，Ser 46磷酸化的缺陷占HSC-3细胞的p53耐药性，并提供证据的机制，在口腔鳞癌的p53耐药性的收购。
To investigate whether dysregulation of p53 phosphorylation confers tumor resistance to p53, we analysed the effects of wild-type p53 on oral squamous cell carcinoma (SCC) cell lines carrying various mutations of p53. Introduction of exogenous p53 neither induced apoptosis nor suppressed colony formation in HSC-3 cells lacking any detectable p53 and HSC-4 cells expressing mutant p53R248Q protein. Consistently, exogenous p53 did not induce proapoptotic p53-target genes in these p53-resistant cells. We found that phosphorylation of exogenous p53 on serine 46 (Ser46) was severely impaired in HSC-3 but not HSC-4 cells. A mutant mimicking Ser46-phosphorylation (p53S46D) enhanced proapoptotic Noxa promoter activity, and overcame the resistance to p53-mediated apoptosis and growth suppression in HSC-3 cells. Conversely, a mutant defective for Ser46-phosphorylation (p53S46A) failed to suppress the growth of p53-sensitive HSC-2 cells. In contrast to HSC-3 cells, p53S46D had no effect on HSC-4 cells, and inhibition of endogenous p53R248Q by siRNA restored p53-mediated apoptosis in HSC-4 cells, indicating a dominant-negative effect of p53R248Q protein on wild-type p53 function. These results demonstrate that the defect in Ser46 phosphorylation accounts for the p53 resistance of HSC-3 cells, and provide evidence for a mechanism underlying the acquisition of p53 resistance in oral SCC.