Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs
Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs
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DOI：
10.1074/jbc.m501664200
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发表时间：
2005-08-26
影响因子：
4.8
通讯作者：
Wiman, KG
中科院分区：
文献类型：
--
作者：
Bykov, VJN;Issaeva, N;Wiman, KG
p53突变体的再激活可能为化疗和放疗耐药肿瘤的治疗提供重要的益处。我们在这里证明了马来酰亚胺衍生分子MIRA-1可以在体外重新激活DNA结合并保持突变p53蛋白的活性构象，并在活细胞中恢复突变p53的转录转激活。MIRA-1在携带四环素调控突变型p53的不同人类肿瘤细胞中诱导p53依赖突变型细胞死亡。结构类似物MIRA-3在体内对SCID小鼠携带p53突变体的肿瘤异种移植物具有抗肿瘤活性。MIRA支架是开发靶向突变p53的抗癌药物的新先导。
Reactivation of mutant p53 is likely to provide important benefits for treatment of chemotherapy- and radio-therapy-resistant tumors. We demonstrate here that the maleimide-derived molecule MIRA-1 can reactivate DNA binding and preserve the active conformation of mutant p53 protein in vitro and restore transcriptional transactivation to mutant p53 in living cells. MIRA-1 induced mutant p53-dependent cell death in different human tumor cells carrying tetracycline-regulated mutant p53. The structural analog MIRA-3 showed antitumor activity in vivo against human mutant p53-carrying tumor xenografts in SCID mice. The MIRA scaffold is a novel lead for the development of anticancer drugs specifically targeting mutant p53.