Role of the p53 homolog p73 in cancer

描述：（由申请人提供）p73具有实质性的结构和 与p53功能同源。p73可以整合多种传入的死亡信号 包括DNA损伤、癌基因失调和T细胞活化 受体，并作为应答介导原代细胞和肿瘤细胞的凋亡。为 例如，我们最近发现，内源性p73是诱导和激活的， 癌基因E2F1、cMyc和ETA。然而，p73在肿瘤发生中的确切作用 是不清楚的，因为目前的遗传和表达数据不支持一个经典的 Knudson型抑制作用。小鼠p73基因受两个启动子调控 P1和P2，P1产生全长p73，P2产生显性阴性 缺失反式激活结构域的deltaNp73。在小鼠中，deltaNp73在小鼠中起作用。 在对抗p53介导神经元死亡中的重要抗凋亡作用 在发育中的大脑的塑造过程中。我们有证据表明人类p73 也有一个功能性P2启动子，它在细胞中产生deltaNp73转录物。 肿瘤的在此，我们假设人p73具有抗肿瘤保护作用， 体内，虽然弱于p53，这是表观遗传，而不是遗传 靶向于肿瘤。我们进一步假设，表观遗传的主要机制 p73靶向是通过p73与p73之间的显性负相互作用介导的。 和i）具有p53突变的肿瘤中的突变p53蛋白（"双重打击"）和ii） p73本身的反式激活缺陷型同种型，如deltaNp73。这 表观遗传模型可以解释i）人类癌症中缺乏p73突变， ii）由于p73基因的频繁肿瘤相关过度表达， 目前尚不清楚显性阴性同种型的贡献，和iii） p73缺陷小鼠未能发生自发性肿瘤，因为 p53的存在可以替代p73的抑制功能。我们将 在人类中使用遗传、功能和生物化学方法来测试这一概念 肿瘤、细胞系和通过产生可诱导的deltaNp73转基因小鼠 模型我们还将探讨其他已建立的人类癌基因是否可以 激活p73。

DESCRIPTION: (provided by applicant) p73 shares substantial structural and functional homology with p53. p73 can integrate diverse incoming death signals in vivo including DNA damage, oncogene deregulation and activation of T cell receptors, and in response mediate apoptosis in primary and tumor cells. For example, we recently showed that endogenous p73 is induced and activated by the oncogenes E2F1, cMyc and EtA. Nevertheless, p73's precise role in tumorigenesis is unclear because current genetic and expression data do not support a classic Knudson-type suppressor role. The mouse p73 gene is regulated by two promoters P1 and P2, with P1 producing full length p73 and P2 producing dominant negative deltaNp73 that lacks the transactivation domain. In mouse, deltaNp73 plays an important anti-apoptotic role in counteracting p53-mediated neuronal death during the sculpting of the developing brain. We have evidence that human p73 also has a functional P2 promoter which is generating deltaNp73 transcripts in tumors. Here we hypothesize that human p73 has an anti-tumor safeguard role in vivo, albeit weaker than p53, which is epigenetically rather than genetically targeted in tumors. We further hypothesize that a main mechanism of epigenetic p73 targeting is mediated through dominant negative interactions between p73 and i) mutant p53 proteins in tumors with p53 mutations ('double hit') and ii) transactivation-deficient isoforms of p73 itself such as deltaNp73. This epigenetic model could explain i) the lack of p73 mutations in human cancer, ii) the frequent tumor-associated overexpression of the p73 gene, since the contribution by dominant negative isoforms is currently not known and iii) the failure of p73-deficient mice to develop spontaneous tumors, because the presence of p53 could substitute for the suppressor function of p73. We will test this notion using genetic, functional and biochemical approaches in human tumors, cells lines and by generating an inducible deltaNp73 transgenic mouse model. We will also explore whether other established human oncogenes can activate p73.