PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

被引：0
作者：
N Rökaeus
J Shen
I Eckhardt
V J N Bykov
K G Wiman
M T Wilhelm
机构：
[1] Cancer Center Karolinska (CCK),Department of Oncology
[2] Karolinska Institutet,Pathology
[3] Tumor and Cell Biology (MTC),Department of Microbiology
[4] Karolinska Institutet,undefined
来源：
Oncogene | 2010年 / 29卷
关键词：
PRIMA-1; APR-246; reactivation; mutant p63; mutant p73; apoptosis;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
The low molecular weight compound PRIMA-1 and the structural analog PRIMA-1MET, also named APR-246, reactivate mutant p53 through covalent binding to the core domain and induce apoptosis in tumor cells. Here, we asked whether PRIMA-1MET/APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. We found that PRIMA-1MET/APR-246 can restore the pro-apoptotic function to mutant TAp63γ and TAp73β in tumor cells but has less effect on TAp73α. Moreover, PRIMA-1MET/APR-246-stimulated DNA binding of mutant TAp63γ and induced expression of the p53/p63/p73 downstream targets p21 and Noxa. The reactivation of mutant p53, p63 and p73 by PRIMA-1MET/APR-246 indicates a common mechanism, presumably involving homologous structural elements in the p53 family proteins. Our findings may open avenues for therapeutic intervention in human developmental disorders with mutations in p63.
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页码：6442 / 6451
页数：9
相关论文
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