The role of p63 and p73 in cancer

描述(申请人提供)：P53控制强大的应激反应，是一种典型的肿瘤抑制因子。P63和p73这两个p53家族成员的发现，引发了人们对其个体和集体功能的许多猜测。然而，尽管这两个基因在癌症中起着重要作用的强烈共识已经存在，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。尽管它们在发育过程中的作用从基因消融研究中立即显现出来，但由于缺乏明确的人类和小鼠基因数据，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，产生多种异构体，可以简单地视为“两个对立的基因合一”。此外，与无处不在的p53突变改变形成鲜明对比的是，p63和p73的特征是几乎没有失活突变，而是在肿瘤中表现出特定亚型的异常表达。这项资助旨在阐明这两个基因在特定致癌环境中的体内作用，并基于两个前提。首先，正常组织在其p63和p73的表达中表现出显著的组织类型和异构体的特异性，这一重要事实到目前为止几乎没有受到关注，但可能掌握着更清楚地了解这两个基因在癌症中的关键。其次，全球p63和p73KO小鼠(缺失所有异构体)可以提供非常多的信息，因为通过取消所有异构体，特定组织中两种相反类别的蛋白质之间的生物主导功能和给定的致癌压力将自行理清并揭示出来。考虑到组织和异构体的特异性，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。目的根据我们的初步数据，p73在原代细胞中作为一种基因组稳定因子发挥着不同于p53的自主作用，它与DNA损伤信号和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无效，我们将确定p73缺失是否会影响B淋巴癌的发生和癌症。目的基于最近发现的TAp63是P53家族中唯一介导DNA损伤诱导的女性生殖细胞凋亡的成员，我们将检验TAp63也保护男性生殖细胞并且在人类睾丸癌(精原细胞瘤和非精原细胞瘤)中是一种肿瘤抑制因子的假设。目的：我们将确定特定类型的人类B淋巴瘤是否存在p63功能缺失突变。此外，通过在现有的致癌小鼠模型中产生p63杂合子，我们将确定p63缺失是否会影响B淋巴母细胞瘤和乳腺癌。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。有充分的证据表明，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。使用具有良好特征的、生理相关的小鼠模型，我们将确定这些基因在几种癌症的发生和发展中的确切作用，包括淋巴瘤、乳腺癌和睾丸癌。这些数据将为治疗干预提供预后标记物和可能的靶标。

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.