Mechanism of p53-dependent Tumor Suppression

p53依赖性肿瘤抑制机制

基本信息

批准号：
10360506
负责人：
Xinbin Chen
金额：
$ 44.3万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10360506
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 Genetic Translation 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 Role Series Serine Signal Transduction Stress TP53 gene Testing The Cancer Genome Atlas Therapeutic Therapeutic Agents Translations Tumor Suppression Tumor-Derived Variant base cell growth in silico in vivo in vivo Model malignant breast neoplasm mouse model mutant neoplastic cell prevent response screening sensor simulation transcription factor tumor progression

项目摘要

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.

项目摘要/摘要 p53肿瘤抑制剂经常在癌症中突变，突变体p53是癌基因。曝光后应力信号（例如DNA损伤），p53转录因子被激活，然后诱导亲卵巢和亲死亡基因。其中是RBM38，一种RNA结合蛋白。有趣的是，我们结果表明，RBM38通过防止EIF4E与p53 M7G帽结合来抑制P53 mRNA翻译。因此，p53和RBM38构成反馈循环。确定p53-RBM38的重要性循环，我们表明：（1）丝氨酸195磷酸化和用天冬氨酸取代S195 （S195D）防止RBM38与EIF4E互动，EIF4E将RBM38从阻遏物转换为 p53翻译激活剂；（2）衍生自RBM38（PEP8：YPYAAS195PA）的8-AA肽和23-- 源自EIF4E（PEP23：AA 195-217）的AA肽能够破坏RBM38-EIF4E复合物增加p53表达。这些观察结果促使我们假设RBM38-EIF4E途径，由S195磷酸化和RBM38中的突变调节，在p53-- 介导的肿瘤抑制。为了测试这一点，我们将确定：（1）如何抑制P53 由RBM38-EIF4E途径调节；（2）RBM38-EIF4E途径是否可以针对杀死带有野生型p53的肿瘤细胞。