The role of p63 and p73 in cancer

标题：p63和p73在癌症中的作用 派：UTE M.Moll，医学博士。 摘要 P53控制着强大的应激反应，是一种典型的肿瘤抑制因子。P63和p63基因的发现 P73是P53家族的两个成员，引起了人们对其个体和集体功能的许多猜测。 然而，尽管存在着强烈的共识，即这两个基因在癌症中发挥着重要作用，但目前的数据是 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，相互矛盾。尽管他们的 从基因消融研究中可以立即看出它们在发育中的作用，描绘了它们在 由于缺乏明确的人类和老鼠的基因数据，癌症仍然难以捉摸。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， 可以简单地理解为“两个对立的基因合而为一”。此外，与无处不在的 P53、P63和P73的突变改变的特征是实际上不存在失活突变， 相反，在肿瘤中表现出特定异构体的异常表达。 这项资助旨在阐明这两个基因在特定致癌背景下的体内作用，并是 基于两个前提。首先，正常组织在其组织类型和亚型上表现出显著的特异性。 P63和p73的表达，这是一个重要的事实，到目前为止很少受到关注，但很可能是 更清楚地了解这两个基因在癌症中的作用。第二，全球p63和p73 KO小鼠(缺少所有 异构体)可以提供非常丰富的信息，因为通过取消所有异构体，在生物上占优势的功能 特定组织中的两类相反的蛋白质和给定的致癌压力会自行理清 并被揭露。 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的体外研究 确定p63和p73在特定人类癌症中的作用。AIM I基于我们的初步数据，p73 发挥自主作用--有别于P53，它是原代细胞中的一种基因组稳定因子，它与 DNA损伤信号和DNA修复。我们将确定其机制和目标。目的II p73的作用 在体内的癌症中。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淋巴母细胞瘤和肿瘤的发生。AIM III基于最近的调查结果 TAp63是P53家族中唯一的成员，它介导DNA损伤诱导的女性细胞凋亡 ，我们将检验TAp63也保护男性生殖系并且是肿瘤抑制因子的假设 在人类睾丸癌(精原细胞瘤和非精原细胞瘤)中。目标四我们将确定是否具体 不同类型的人类B淋巴瘤存在p63功能缺失突变。此外，通过生成P63 在现有的致癌小鼠模型中，我们将确定p63丢失是否影响B- 淋巴增生症和乳腺癌。P53基因控制着强大的应激反应，是一种典型的肿瘤 人类癌症中的抑制子。有充分的证据表明，这两起案件 被称为p63和p73的基因在人类癌症中也起着关键作用。使用得当 特征化的、生理相关的小鼠模型，我们将定义 这些基因与几种癌症的发生和发展有关，包括 淋巴瘤、乳腺癌和睾丸癌。这些数据将提供预后标志和 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.