The role of p63 and p73 in cancer

p63和p73在癌症中的作用 PI：Ute M. Moll，医学博士 摘要 p53控制强大的应激反应，是典型的肿瘤抑制因子。p63的发现， p73是p53家族中的两个成员，引起了人们对其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，但目前的数据表明， 它们的性质是否是肿瘤抑制性的、致癌的或在某些情况下两者都是矛盾的。虽然他们的 从基因切除研究中可以立即看出它们在发育中的作用， 由于缺乏人类和小鼠的明确遗传数据，癌症仍然难以捉摸。由于第二次内部 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， 可以简单地看作是“两个对立的基因合二为一”。此外，与无处不在的 p53、p63和p73的突变改变的特征在于实际上不存在失活突变， 而是在肿瘤中表现出特异性同种型的异常表达。 该基金旨在阐明这两种基因在特定致癌背景下的体内作用， 基于两个前提。首先，正常组织在其组织类型和亚型方面表现出惊人的特异性。 p63和p73的表达，一个重要的事实，到目前为止很少受到关注，但可能是关键， 更清楚地了解这两个基因在癌症中的作用。第二，全局p63和p73 KO小鼠（缺失所有 同种型）可以是非常有信息性的，因为通过取消所有同种型， 特定组织内的两类相反的蛋白质和特定的致癌压力会自行分离 并被揭露出来 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 以确定p63和p73在特定人类癌症中的作用。目的I基于我们的初步数据，p73 发挥自主作用-与p53不同  作为原代细胞中的基因组稳定因子， DNA损伤信号和DNA修复。我们将确定其机制和目标。第二章p73的作用 in cancer癌症in vivo体内.通过在现有的致癌小鼠模型中产生p73缺失，我们将确定 p73缺失是否影响B淋巴瘤发生和癌。目标三根据最近的调查结果， TAp 63是p53家族中唯一介导DNA损伤诱导的女性细胞凋亡的成员 生殖系，我们将测试TAp 63也保护雄性生殖系并且是肿瘤抑制因子的假设 在人类睾丸癌（睾丸癌和非睾丸癌）中。目标四我们将确定是否具体 人类B淋巴瘤的种类维持p63功能丧失突变。此外，通过生成p63 在现有的致癌小鼠模型中，我们将确定p63缺失是否影响B- 淋巴瘤和乳腺癌。p53基因控制着强大的应激反应，是典型的肿瘤。 人类癌症的抑制基因。有充分的证据表明，两个相关的 被称为p63和p73的基因在人类癌症中也起着关键作用。使用公 特征化的，生理学相关的小鼠模型，我们将定义 这些基因在几种癌症的发展和进展中，包括 淋巴瘤乳腺癌和睾丸癌这些数据将提供预后标志物， 可能是治疗干预的目标。

Title: the Role of p63 and p73 in Cancer PI: Ute M. Moll, M.D. Abstract 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. 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.