Mechanism of p53-dependent Tumor Suppression

项目摘要/摘要 P53抑癌基因在肿瘤中经常发生突变，突变型P53是一种癌基因。在暴露后 对于压力信号，如DNA损伤，P53转录因子被激活，然后诱导一系列 支持生存和支持死亡的基因。其中包括Rbm38，一种RNA结合蛋白。有趣的是，我们 结果表明，Rbm38通过阻止eIF4E与P53 m7G帽结合来抑制P53 mRNA的翻译。 因此，P53和Rbm38构成了一个反馈环。确定P53-Rbm38的意义 环，我们发现：(1)丝氨酸-195的磷酸化和S195被天冬氨酸取代 (S195D)防止Rbm38与eIF4E交互，eIF4E将Rbm38从抑制器转换为 (2)源于Rbm38的8-AA多肽(Pep8：YPYAAS195PA)和23-AAA。 来源于eIF4E(Pep23：aA195-217)的AA肽能够破坏Rbm38-eIF4E复合体 增加P53的表达。这些观察促使我们假设Rbm38-eIF4E途径， 受Rbm38的S195磷酸化和突变调控，在P53中起关键作用。 介导性肿瘤抑制。为了测试这一点，我们将确定：(1)P53依赖的肿瘤抑制如何 受Rbm38-eIF4E通路调控；(2)Rbm38-eIF4E通路是否可以靶向 杀死携带野生型p53的肿瘤细胞。

Project Summary/Abstract p53 tumor suppressor is frequently mutated in cancer, and mutant p53 is an oncogene. Upon exposure to a stress signal, such as DNA damage, p53 transcription factor is activated and then induces an array of pro-survival and pro-death genes. Among these is Rbm38, a RNA-binding protein. Interestingly, we showed that Rbm38 represses p53 mRNA translation by preventing eIF4E from binding to p53 m7G cap. Thus, p53 and Rbm38 constitutes a feedback loop. To determine the significance of the p53-Rbm38 loop, we showed that:(1) phosphorylation of serine-195 and substitution of S195 with aspartic acid (S195D) prevent Rbm38 from interacting with eIF4E, which converts Rbm38 from a repressor to an activator of p53 translation; (2) an 8-aa peptide derived from Rbm38 (Pep8: YPYAAS195PA) and a 23- aa peptide derived from eIF4E (Pep23: aa 195-217) are able to disrupt the Rbm38-eIF4E complex to increase p53 expression. These observations prompt us to hypothesize that the Rbm38-eIF4E pathway, which is regulated by S195 phosphorylation and mutations in Rbm38, plays a critical role in p53- mediated tumor suppression. To test this, we will determine: (1) how p53-dependent tumor suppression is regulated by the Rbm38-eIF4E pathway; (2) whether the Rbm38-eIF4E pathway can be targeted to kill tumor cells carrying wild-type p53.