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

流行病学研究强烈表明，慢性应激对人的健康有显著的负面影响。 人类肿瘤的发病、进展和死亡率。然而，慢性的作用和潜在的机制， 肿瘤发生中应激仍然是难以捉摸的。在小鼠中采用慢性束缚， 诱导慢性应激，我们发现慢性应激促进IR诱导的小鼠淋巴瘤形成。 抑癌基因p53及其信号通路在肿瘤抑制中起着重要作用。我们最近的研究 发现慢性束缚大大降低了野生型p53（wtp 53）蛋白的水平和功能，这是一个 慢性应激促进含有WTP 53的肿瘤发生的重要机制。p53是 人类肿瘤中最常发生突变的基因;超过50%的肿瘤含有p53突变。许多 肿瘤相关突变型p53（mutp 53）蛋白不仅丧失了wtp 53的肿瘤抑制功能， 还获得新的活性以促进肿瘤发生，定义为功能获得（GOF）。Mutp 53蛋白通常 在肿瘤中积累到高水平，这对mutp 53 GOF至关重要。有趣的是，我们的初步数据显示 慢性应激促进肿瘤发生中mutp 53蛋白的积累和GOF。慢性压力结果 肾上腺素能受体（-AR）及其信号通路的激活 来调节慢性压力的影响。我们的初步研究表明，儿茶酚胺介导的 慢性应激对mutp 53蛋白积累和GOF的促进作用。根据我们初步的 研究中，我们假设慢性应激促进肿瘤发生，而mutp 53的上调 蛋白质水平和GOF在肿瘤发生中由儿茶酚胺是一个重要的潜在机制 对于含有mutp 53的肿瘤。在这项拟议的研究中，我们将1）测试慢性压力的假设， 通过促进mutp 53积累，优先促进含有mutp 53的肿瘤的肿瘤发生 通过小鼠肿瘤模型检测mutp 53蛋白表达上调对卵巢癌和GOF的抑制作用; 2）检测mutp 53蛋白表达上调对卵巢癌和GOF的抑制作用。 水平和GOF的儿茶酚胺是一个重要的机制，慢性应激促进 在含有mutp 53的肿瘤中的肿瘤发生; 3）确定儿茶酚胺促进肿瘤发生的机制。 mutp 53积累和GOF。我们希望这项研究能提供直接证据， 促进含mutp 53的肿瘤的肿瘤发生，并证实mutp 53蛋白的上调 水平和GOF的一个重要机制。阻断慢性应激和/或-AR 信号传导可能是含mutp 53的肿瘤的新的治疗策略。这项研究有可能 提供关键的分子靶点，用于破坏肿瘤微环境中的应激/神经激素信号传导 以治疗含有不可用药的mutp 53的肿瘤。

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.