The role of p63 and p73 in cancer

描述（由申请人提供）：p53控制强大的应激反应，是典型的肿瘤抑制因子。p53家族中两个成员p63和p73的发现引起了人们对它们的个体和集体功能的许多猜测。然而，尽管存在强烈的共识，即这两种基因在癌症中起主要作用，但目前的数据是相互矛盾的，无论它们的性质是肿瘤抑制，致癌还是在某些情况下两者兼而有之。尽管它们在发育中的功能从基因消融研究中立即显现出来，但由于缺乏人类和小鼠的明确遗传数据，描绘它们在癌症中的确切作用仍然难以捉摸。由于第二个内部启动子和选择性剪接，p63和p73是复杂的双极基因，产生多种亚型，可以简单地被视为“两个相反的基因在一个”。此外，与p53的普遍突变改变形成鲜明对比，p63和p73的特征在于几乎不存在失活突变，而是在肿瘤中表现出特异性同种型的异常表达。这项资助旨在阐明这两种基因在特定致癌背景下的体内作用，并基于两个前提。首先，正常组织在其p63和p73表达中表现出对组织类型和亚型的显著特异性，这是一个重要的事实，迄今为止很少受到关注，但可能是更清楚地了解这两个基因在癌症中的关键。第二，全局p63和p73 KO小鼠（缺失所有同种型）可以提供非常多的信息，因为通过消除所有同种型，特定组织内两种相反类型的蛋白质之间的生物学主导功能和给定的致癌应激将自行整理并被揭示。考虑到组织和亚型特异性，我们将使用小鼠遗传学和细胞生物学体外研究来确定p63和p73在特定人类癌症中的作用。目的1基于我们的初步数据，p73在原代细胞中作为基因组稳定因子发挥自主作用-不同于p53 -，其与DNA损伤信号传导和DNA修复有关。我们将确定其机制和目标。目的研究p73在体内肿瘤中的作用。通过在现有的致癌小鼠模型中产生p73缺失，我们将确定p73缺失是否会影响B淋巴瘤的发生和癌变。目的III基于最近发现TAp 63是p53家族中介导女性生殖系中DNA损伤诱导的凋亡的唯一成员，我们将测试TAp 63也保护男性生殖系并且是人类睾丸癌（腺瘤和非腺瘤）中的肿瘤抑制因子的假设。目的四，我们将确定是否特定类别的人类B淋巴瘤维持p63功能丧失突变。此外，通过在现有的致癌小鼠模型中产生p63杂合性，我们将确定p63缺失是否影响B-淋巴瘤发生和乳腺癌。公共卫生相关性：p53基因控制着强大的应激反应，是人类癌症中典型的肿瘤抑制因子。有足够的证据表明，两个相关的基因，称为p63和p73，也在人类癌症中发挥关键作用。使用良好的特征，生理相关的小鼠模型，我们将定义这些基因在几种癌症的发展和进展中的确切作用，包括淋巴瘤，乳腺癌和睾丸癌。这些数据将提供预后指标和可能的治疗干预的目标。

DESCRIPTION (provided by applicant): p53 controls a powerful stress response and is a quintessential tumor suppressor. The discovery of p63 and p73, two p53 family members, provoked much speculation about their individual and collective functions. However, while a strong consensus exists that both genes play a major role in cancer, current data is conflicting whether their nature is tumor suppressive, oncogenic or in some context both. Although their function in development was immediately apparent from gene ablation studies, delineating their exact role in cancer remains elusive due to a lack of clear genetic data in humans and mice. Due to a second internal promoter and alternative splicing, p63 and p73 are complex bipolar genes giving rise to multiple isoforms that can simplistically be viewed as "Two Opposing-Genes-in-One". Moreover, in sharp contrast to the ubiquitous mutational alteration of p53, p63 and p73 are characterized by a virtual absence of inactivating mutations, and instead exhibit aberrant expression of specific isoforms in tumors. This grant aims at elucidating the in vivo role of both genes in specific oncogenic contexts and is based on two premises. First, normal tissues exhibit a striking specificity for tissue types and isoforms in their p63 and p73 expression, an important fact that up to now received little attention, yet likely holds the key to a clearer understanding of these two genes in cancer. Second, global p63 and p73 KO mice (missing all isoforms) can be very informative, since by canceling all isoforms, the biologically dominant function among the two opposing classes of proteins within a specific tissue and a given oncogenic stress will sort itself out and be revealed. Mindful of tissue and isoform specificity, we will use mouse genetics and cell biological in vitro studies to determine the role of p63 and p73 in specific human cancers. Aim I Based on our preliminary data, p73 plays an autonomous role - distinct from p53 - as a genomic stability factor in primary cells, which is linked to DNA damage signaling and DNA repair. We will identify its mechanisms and targets. Aim II The role of p73 in cancer in vivo. By generating p73 nullizygosity in existing oncogenic mouse models, we will determine whether p73 loss influences B-lymphomagenesis and carcinomas. Aim III Based on the recent finding that TAp63 is the unique member of the p53 family that mediates DNA damage-induced apoptosis in the female germ line, we will test the hypothesis that TAp63 also protects the male germ line and is a tumor suppressor in human testicular cancers (seminomas and non-seminomas). Aim IV We will determine whether specific classes of human B-lymphomas sustain p63 loss-of-function mutations. Also, by generating p63 heterozygosity in existing oncogenic mouse models, we will determine whether p63 loss influences B- lymphomagenesis and breast cancer. PUBLIC HEALTH RELEVANCE: The p53 gene controls a powerful stress response and is a quintessential tumor suppressor in human cancers. There is ample evidence to suggest that two related genes, called p63 and p73, also play crucial roles in human cancer. Using well characterized, physiologically relevant mouse models, we will define the precise role of these genes in the development and progression of several cancers, including lymphoma, breast and testicular cancer. These data will provide prognostic markers and possibly targets for therapeutic intervention.