Frequent phosphorylation at serine 392 in overexpressed p53 protein due to missense mutation in carcinoma of the urinary tract
Frequent phosphorylation at serine 392 in overexpressed p53 protein due to missense mutation in carcinoma of the urinary tract
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DOI：
10.1002/path.1082
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发表时间：
2002-05-01
影响因子：
7.3
通讯作者：
Shuin, T
中科院分区：
文献类型：
--
作者：
Furihata, M;Kurabayashi, A;Shuin, T
通过磷酸化对P53进行转录后修饰已被认为是P53稳定和功能调节的重要机制。特别是，P53 Ser392的磷酸化通过稳定P53四聚体的形成来激活特定的DNA结合功能。本研究探讨了尿路上皮移行细胞癌(TCC)中P53 Ser392磷酸化与P53错义突变类型的关系，并根据P53蛋白晶体结构所揭示的功能域对突变进行了分层。在41例错义突变的膀胱移行细胞癌中，26例(63.4%)对Ser392磷酸化P53抗体呈免疫阳性反应。与结构突变相比，第7外显子错义突变(p=0.0307)或位于影响DNA直接结合能力的区域(p=0.0273)与Ser392免疫阳性显著相关。未发现Ser392免疫反应与其他不同类型的P53突变之间有统计学意义的关系。在高级别(p<；0.0001)和晚期(p=0.0119)的膀胱移行细胞癌中，Ser392免疫染色阳性的病例的发生率高于野生型p53的膀胱移行细胞癌。尿路上皮TCC中Ser392免疫反应性与细胞凋亡指数无明显相关性。这些体内研究结果表明，在膀胱移行细胞癌中，Ser392的磷酸化经常发生在突变型P53中。由于突变型P53可以通过与野生型P53的异源齐聚起显性-负性作用，这些发现也提示Ser392的磷酸化可能激活四聚体的形成，从而促进突变型P53的显性-负性作用，从而促进侵袭性膀胱癌的增殖。版权所有(C)2002 John Wiley Sons，Ltd.
Post-transcriptional modification of p53 by phosphorylation has been proposed to be an important mechanism of p53 stabilization and functional regulation. Phosphorylation of p53 Ser392, in particular, activates specific DNA binding functions by stabilizing p53 tetramer formation. This study evaluated the relationship between p53 Ser392 phosphorylation and various types of p53 missense mutation detected in urothelial transitional cell carcinomas (TCCs), with stratification of the mutations according to the functional domains elucidated by the crystal structure of the p53 protein. Of 41 TCCs with missense mutations, 26 (63.4%) exhibited immunopositivity with Ser392 phospho-specific p53 antibody. In comparison to structural mutations, the missense mutations at exon 7 (p=0.0307) or located in regions that affect direct DNA binding ability (p = 0.0273) were significantly associated with Ser392 immunopositivity. No statistically significant relationship was found between Ser392 immunoreactivity and other different types of p53 mutation. The prevalence of cases exhibiting Ser392-positive immunostaining was higher for high-grade (p < 0.0001) and advanced-stage TCCs (p = 0.0119) than for TCCs with wild-type p53. No significant relationship was found between Ser392 immuno reactivity and apoptotic index in urothelial TCCs. These in vivo findings indicate that Ser392 phosphorylation frequently occurs in mutant form p53 in TCCs. Because mutant form p53 can act dominant-negatively by hetero-oligomerization with wild-type p53, these findings also suggest that Ser392 phosphorylation might activate tetramer formation to promote the dominant-negative effects of mutant form p53, and thereby contribute to proliferation of aggressive TCCs. Copyright (C) 2002 John Wiley Sons, Ltd.