Novel effectors of Kras in oncogenesis, senescence and tumor progression

Kras 在肿瘤发生、衰老和肿瘤进展中的新效应子

基本信息

批准号：
8512665
负责人：
Eric Alejandro Sweet-Cordero
金额：
$ 25.41万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512665
关键词：
Biochemical Cancer Biology Cancer cell line Cell Aging Cells Colon Carcinoma DNA Damage Data Event GTP-Binding Proteins Genes Genetic Goals HTRA2 gene Human KRAS2 gene Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Messenger RNA Molecular Molecular Genetics Mus Mutate Mutation Nephroblastoma Oncogenes Oncogenic Outcome PTEN gene Phenotype Phosphorylation Play Post-Transcriptional Regulation Proliferating Protein Biosynthesis Protein Splicing Proteins RNA Splicing Regulation Resistance Role Serine Protease Signal Pathway Testing Tissues Translations Up-Regulation WT1 gene base cancer initiation cancer therapy chemotherapy functional genomics in vivo Model innovation mouse model neoplastic cell novel novel therapeutic intervention response senescence tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): KRAS is one of the most frequently mutated human oncogenes. In some settings oncogenic KRAS can trigger cellular senescence, whereas in others expression leads to hyperproliferation. Given the importance of KRAS mutation in human cancer, elucidating the mechanisms regulating these two drastically distinct outcomes would help identify novel therapeutic approaches in RAS-driven cancers. We have identified a novel role for Wilms tumor-1 (WT1) as a critical regulator of senescence and proliferation downstream of oncogenic KRAS. Loss of Wt1 leads to senescence in mouse primary cells and human tumor cells in an oncogenic KRAS- dependent manner. In addition, WT1 expression is specifically upregulated in chemoresistant tumor cells in a mouse model of lung cancer. These findings reveal an unexpected role for WT1 as a key regulator of the genetic network downstream of KRAS and suggest a key role for Wt1 in chemoresistance. In this proposal, we will use a combination of molecular, genetic and biochemical approaches to elucidate the mechanistic basis for the observed interaction between oncogenic KRAS and WT1. Preliminary data suggests that at least part of the role of WT1 is mediated by post-transcriptional regulation of RNAs. Thus, this proposal will use state-of- the-art approaches to analyze the role of Wt1 on splicing and protein translation. In addition, we will determine the role of WT1 in regulating chemotherapy resistance in KRAS-driven lung tumors.

描述（由申请人提供）：KRAS 是最常突变的人类癌基因之一。在某些情况下，致癌 KRAS 可以引发细胞衰老，而在其他情况下，表达会导致过度增殖。鉴于 KRAS 突变在人类癌症中的重要性，阐明调节这两种截然不同的结果的机制将有助于确定 RAS 驱动的癌症的新治疗方法。我们已经确定了肾母细胞瘤-1 (WT1) 作为致癌 KRAS 下游衰老和增殖的关键调节因子的新作用。 Wt1 的缺失会导致小鼠原代细胞和人类肿瘤细胞以致癌 KRAS 依赖性方式衰老。此外，在肺癌小鼠模型的化疗耐药肿瘤细胞中，WT1 表达特异性上调。这些发现揭示了 WT1 作为 KRAS 下游遗传网络关键调节因子的意想不到的作用，并表明 Wt1 在化疗耐药中的关键作用。在本提案中，我们将结合分子、遗传和生化方法来阐明观察到的致癌 KRAS 和 WT1 之间相互作用的机制基础。初步数据表明，WT1 的至少部分作用是由 RNA 转录后调控介导的。因此，该提案将使用最先进的方法来分析 Wt1 在剪接和蛋白质翻译中的作用。此外，我们将确定 WT1 在调节 KRAS 驱动的肺部肿瘤化疗耐药中的作用。