A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo
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DOI：
10.1172/jci28920
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Ryan, Kevin M.
中科院分区：
文献类型：
--
作者：
Bell, Helen S.;Dufes, Christine;Ryan, Kevin M.
肿瘤抑制基因P53是肿瘤细胞死亡的有效诱导者，目前已有利用P53获得治疗收益的策略。然而，由于大约一半的人类癌症含有突变的p53，这些策略的应用受到限制。P53家族成员，特别是p73，在许多方面都是P53的功能类似物，但在癌症中很少发生突变。然而，p73的特异性激活方法仍有待阐明。我们在这里描述了一种最小的P53衍生的凋亡肽，它诱导多种细胞类型的死亡，而不考虑P53的状态。虽然不能直接激活基因表达，但该肽保留了结合iASPP的能力--iASPP是P53家族成员常见的负调控因子。与此相一致的是，在P53缺失的细胞中，该肽去抑制p73，导致p73介导的基因激活和死亡。此外，表达该多肽的转基因系统纳米颗粒通过p73在体内引起肿瘤消退。因此，这项研究预示着我们认为是第一个直接和选择性地激活p73治疗的策略，并可能导致广泛适用于治疗恶性疾病的药物的开发。
The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP - a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.