The role of chronic stress in regulation of mutant p53 and tumorigenesis

慢性应激在突变p53和肿瘤发生调节中的作用

• 批准号: 9235478
• 负责人: Wenwei Hu
• 金额: $ 36.33万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235478
• 关键词: Adrenergic Receptor; Animal Model; BAG2 gene; Binding Proteins; Biological Models; Catecholamines; Chronic; Chronic stress; Data; Development; Down-Regulation; Epinephrine; Genes; Glucocorticoids; Goals; Human; Knock-in Mouse; Lymphoma; MDM2 gene; Mediating; Metastatic Neoplasm to the Lung; Modeling; Molecular; Molecular Target; Mus; Mutate; Mutation; Neoplasm Metastasis; Neurohormones; Norepinephrine; Patients; Play; Protein p53; Proteins; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Stress; TP53 gene; Testing; Tumor Suppression; Up-Regulation; base; epidemiology study; gain of function; human mortality; in vivo; knock-down; mouse model; mutant; novel; novel therapeutics; restraint; subcutaneous; tumor; tumor growth; tumor microenvironment; tumor progression; tumor xenograft; tumorigenesis; ubiquitin-protein ligase

Epidemiological studies strongly suggest that chronic stress has significant negative influences on the onset, progression and mortality of human tumors. However, the role and underlying mechanisms of chronic stress in tumorigenesis remain elusive. Employing chronic restraint in mice, a well-established mouse model to induce chronic stress, we found that chronic stress promotes IR-induced lymphoma formation in mice. Tumor suppressor p53 and its signaling pathway play a critical role in tumor suppression. Our recent studies found that chronic restraint greatly decreases wild type p53 (wtp53) protein levels and function, which is an important mechanism by which chronic stress promotes tumorigenesis in tumors containing wtp53. p53 is the most frequently-mutated gene in human tumors; over 50% of all tumors harbor p53 mutations. Many tumor-associated mutant p53 (mutp53) proteins not only lose the tumor suppressive function of wtp53, but also gain new activities to promote tumorigenesis, defined as gain-of-function (GOF). Mutp53 proteins often accumulate to high levels in tumors which is critical for mutp53 GOF. Interestingly, our preliminary data show that chronic stress promotes mutp53 protein accumulation and GOF in tumorigenesis. Chronic stress results in the prolonged elevation of catecholamines, which activates -adrenergic receptor ( -AR) and its signaling to mediate many effects of chronic stress. Our preliminary studies suggest that catecholamines mediate the promoting effect of chronic stress on mutp53 protein accumulation and GOF. Based on our preliminary studies, we hypothesize that chronic stress promotes tumorigenesis, and the up-regulation of mutp53 protein levels and GOF in tumorigenesis by catecholamines is an important underlying mechanism for tumors containing mutp53. In this proposed study, we will 1) test the hypothesis that chronic stress preferentially promotes tumorigenesis in tumors containing mutp53 through promoting mutp53 accumulation and GOF by employing mouse tumor models; 2) test the hypothesis that the up-regulation of mutp53 protein levels and GOF by catecholamines is an important mechanism by which chronic stress promotes tumorigenesis in tumors containing mutp53; 3) determine the mechanisms by which catecholamines promote mutp53 accumulation and GOF. We expect that this study will provide direct evidence that chronic stress promotes tumorigenesis of mutp53 containing tumors, and validate that the up-regulation of mutp53 protein levels and GOF by catecholamines is an important mechanism. Blocking chronic stress and/or -AR signaling could be a novel therapeutic strategy for mutp53 containing tumors. This study has the potential to provide pivotal molecular targets for disrupting stress/neurohormone signaling in the tumor microenvironment to treat undruggable mutp53 containing tumors.

流行病学研究有力地表明，慢性应激对健康有显著的负面影响