Mechanism of p53-dependent Tumor Suppression

p53依赖性肿瘤抑制机制

• 批准号: 10574526
• 负责人: Xinbin Chen
• 金额: $ 44.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574526
• 关键词: Aspartic Acid; Binding; Biology; Canis familiaris; Cell Aging; Cell Line; Cells; Cessation of life; Charge; Complex; DNA Damage; Databases; Exposure to; Feedback; Genes; Health; Human; Hydrogen Bonding; In Vitro; Knock-in; Knock-in Mouse; Large Intestine Carcinoma; Lymphoma; Lysine; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Mus; Mutate; Mutation; Oncogenes; Pathway interactions; Peptides; Phosphorylation; Play; Premature aging syndrome; RNA-Binding Proteins; Regulation; Repression; Role; Series; Serine; Signal Transduction; Stress; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Agents; Translations; Tumor Suppression; Tumor-Derived; Variant; cell growth; in silico; in vivo; in vivo Model; mRNA Translation; malignant breast neoplasm; mouse model; mutant; neoplastic cell; prevent; response; screening; sensor; simulation; transcription factor; tumor progression

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.

项目总结/摘要 p53肿瘤抑制基因在癌症中经常突变，突变型p53是一种致癌基因。在暴露 对于应激信号，如DNA损伤，p53转录因子被激活，然后诱导一系列的 促生存和促死亡基因其中之一是Rbm 38，一种RNA结合蛋白。有趣的是，我们 结果表明，Rbm 38通过阻止eIF 4 E与p53 m7 G帽结合来抑制p53 mRNA的翻译。 因此，p53和Rbm 38构成反馈回路。为了确定p53-Rbm 38在乳腺癌中的意义， 环中，我们发现：（1）丝氨酸-195的磷酸化和S195被天冬氨酸取代 （S195 D）阻止Rbm 38与eIF 4 E相互作用，eIF 4 E将Rbm 38从阻遏物转化为抑制物。 p53翻译的激活剂;（2）来源于Rbm 38的8-aa肽（Pep 8：YPYAAS 195 PA）和来源于Rbm 38的23-aa肽（Pep 8：YPYAAS 195 PA）。 源自eIF 4 E的aa肽（Pep 23：aa 195-217）能够破坏Rbm 38-eIF 4 E复合物， 增加p53表达。这些观察结果促使我们假设Rbm 38-eIF 4 E途径， 受S195磷酸化和Rbm 38突变的调节，在p53- 介导的肿瘤抑制。为了验证这一点，我们将确定：（1）p53依赖性肿瘤抑制 受Rbm 38-eIF 4 E通路调节;（2）Rbm 38-eIF 4 E通路是否可以靶向 杀死携带野生型p53的肿瘤细胞。