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首页> 外文期刊>Cell cycle >Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA.
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Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA.

机译：小分子RITA对突变体p53的凋亡诱导功能的挽救。

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摘要

Expression of mutant p53 correlates with poor prognosis in many tumors, therefore strategies aimed at reactivation of mutant p53 are likely to provide important benefits for treatment of tumors that are resistant to chemotherapy and radiotherapy. We have previously identified and characterized a small molecule RITA which binds p53 and induces a conformational change which prevents the binding of p53 to several inhibitors, including its own destructor MDM2. In this way, RITA rescues the tumor suppression function of wild type p53. Here, we demonstrate that RITA suppressed the growth and induced apoptosis in human tumor cell lines of a diverse origin carrying mutant p53 proteins. RITA restored transcriptional transactivation and transrepression function of several hot spot p53 mutants. The ability of RITA to rescue the activity of different p53 mutants suggests its generic mechanism of action. Thus, RITA is a promising lead for the development of anti-cancer drugs that reactivate the tumor suppressor function of p53 in cancer cells irrespective whether they express mutant or wild type p53.
机译：突变体p53的表达与许多肿瘤的预后不良相关，因此，旨在重新激活突变体p53的策略可能为治疗对化学疗法和放射疗法有抵抗力的肿瘤提供重要的好处。我们之前已经确定并鉴定了一个小分子RITA，它可以结合p53并诱导构象变化，从而阻止p53与几种抑制剂（包括其自身的破坏物MDM2）结合。通过这种方式，RITA可以挽救野生型p53的肿瘤抑制功能。在这里，我们证明了RITA抑制了携带突变p53蛋白的多种来源的人肿瘤细胞系的生长并诱导了细胞凋亡。 RITA恢复了几个热点p53突变体的转录反式激活和反转录功能。 RITA抢救不同p53突变体的活性的能力表明其通用的作用机制。因此，RITA是开发抗癌药物的有希望的先导，无论它们表达突变型还是野生型p53，该抗癌药都能重新激活癌细胞中p53的肿瘤抑制功能。

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