DNA Damage Retinoblastoma and Cell Survival

描述：（由申请人提供）视网膜母细胞瘤（Rb）基因是 在许多形式的癌症中功能失活，如乳腺癌， 小细胞肺癌，代表了典型的肿瘤抑制因子。在 Rb除了其肿瘤抑制活性外还抑制细胞周期进程， 对于DNA损伤后诱导细胞周期停滞是必需的，并抑制 细胞死亡Rb的生物学效应的复杂性与 多样性：结合Rb的蛋白质。Rb与许多蛋白质结合，包括 E2 F-1、肿瘤病毒蛋白如SV 40大T抗原、c-Abl、MDM 2和 组蛋白脱乙酰酶。虽然Rb抑制细胞死亡的观察结果是 差不多九岁的时候，我们对潜在分子机制的理解 保持模糊。我们已经发现Rb突变体保留了抑制 细胞周期进展，但不促进DNA损伤后的细胞存活。这些 研究使我们提出了一个模型，Rb的抗凋亡活性， Rb在DNA损伤后促进细胞存活的能力是通过 Rb的LxCxE结合位点。在这一建议中，我们将进一步发展我们的 Rb-LxCxE相互作用在细胞中起重要作用的假设 DNA损伤后的生存我们将研究Rb-LxCxE的一般性 DNA损伤后细胞存活相互作用及其生物学意义 通过产生表达突变Rb转基因的Rb-I-小鼠， 不能结合含有LxCxE基序的蛋白质。我们将描述 Rb参与的凋亡信号通路（Rb-LxCxE相互作用）促进 细胞存活Rb-LxCxE相互作用与其它Rb Rb生存途径中的结合蛋白也将被阐明。这些 研究将影响我们对Rb在细胞生物学功能中的理解 和人类癌症中。

DESCRIPTION: (provided by applicant) The Retinoblastoma (Rb) gene is functionally inactivated in many forms of cancer, like breast carcinoma and small cell lung carcinoma, and represents the prototypical tumor suppressor. In addition to its tumor suppressor activity Rb inhibits cell cycle progression, is essential for induction of cell cycle arrest after DNA damage and inhibits cell death. The complexity of biological effects of Rb is matched by the diversity of: proteins which bind Rb. Rb binds a number of proteins, including E2F-1, oncoviral proteins like the SV4O large T antigen, c-Abl, MDM2 and histone deacetylases. Although the observation that Rb inhibits cell death is almost nine years old, our understanding of the underlying molecular mechanisms remain obscure. We have found Rb mutants which retain the ability to inhibit cell cycle progression but do not promote cell survival after DNA damage. These studies have led us to propose a model of the anti-apoptotic activity of Rb in which the ability of Rb to promote cell survival after DNA damage is mediated by the LxCxE binding site of Rb. In this proposal we will further develop our hypothesis that the Rb-LxCxE interaction plays an essential role in cell survival after DNA damage. We will examine the generality of Rb-LxCxE interaction in cell survival after DNA damage and establish its biological significance by generating Rb -I- mice which express a mutant Rb transgene that is unable to bind LxCxE motif containing proteins. We will characterize the apoptosis signaling pathways engaged by Rb (Rb-LxCxE interaction) to promote cell survival. The relationship between the Rb-LxCxE interaction and other Rb binding proteins in the Rb survival pathway will also be clarified. These studies will impact our understanding of Rb in its cell biological functions and in human cancer.