A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines
A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines
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DOI：
10.1006/jmbi.2000.3738
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发表时间：
2000-05-26
影响因子：
5.6
通讯作者：
Fabbro, D
中科院分区：
文献类型：
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作者：
Chène, P;Fuchs, J;Fabbro, D
hdm2蛋白负向调节p53肿瘤抑制活性。与p53结合后，hdm2刺激p53降解并抑制其转录活性。此外，hdm2蛋白在多种肿瘤中过表达，使p53失活。我们在这里报道了一种来自p53的八聚体合成肽在体外抑制p53-hdm2相互作用。在细胞实验中，这种未标记的肽能穿透肿瘤细胞并诱导p53的积累。p53的积累导致它的激活。p53转录调节的两个基因产物p21（Waf1/Cip1）和hdm2在多肽的存在下被诱导。当与过度表达hdm2的肿瘤细胞一起使用时，该肽通过凋亡诱导这些肿瘤细胞死亡。这种肽的作用方式不同于dna损伤剂（如顺铂），因为它不会诱导p53在丝氨酸15上的磷酸化。这项工作用低分子质量分子验证了我们目前关于hdm2蛋白调控p53通路的知识。研究还表明，p53-hdm2相互作用的抑制剂是激活野生型p53肿瘤中p53通路的非常有吸引力的候选者。(C) 2000年学术出版社。
The hdm2 protein negatively regulates p53 tumour suppressor activity. Upon binding to p53, hdm2 stimulates p53 degradation and inhibits its transcriptional activity. Moreover, the hdm2 protein is overexpressed in various tumours inactivating p53. We report here that an octamer synthetic peptide derived from p53 inhibits the p53-hdm2 interaction in vitro. In cellular assays, this untagged peptide penetrates tumour cells and induces the accumulation of p53. The accumulation of p53 leads to its activation. Two gene products transcriptionally regulated by p53, p21(Waf1/Cip1) and hdm2, are induced in the presence of the peptide. When used with tumour cells that overexpress hdm2, the peptide induces the death of these tumour cells by apoptosis. The mode of action of this peptide differs from that of DNA-damaging agents (e.g. cisplatin) in that it does not induce p53 phosphorylation on serine 15. This work validates with a low molecular mass molecule our current knowledge on the regulation of the p53 pathway by the hdm2 protein. It also shows that inhibitors of the p53-hdm2 interaction are very attractive candidates for the activation of the p53 pathway in tumours expressing wild-type p53. (C) 2000 Academic Press.