DNA Damage Retinoblastoma and Cell Survival

DNA 损伤视网膜母细胞瘤和细胞存活

• 批准号: 6478030
• 负责人: ARUN FOTEDAR
• 金额: $ 37.7万
• 依托单位: SIDNEY KIMMEL CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6478030
• 关键词: DNA damage; apoptosis; biological signal transduction; genetically modified animals; laboratory mouse; microarray technology; mutant; neoplasm /cancer genetics; nuclear factor kappa beta; protein protein interaction; protein structure function; recombinant proteins; retinoblastoma; retinoblastoma protein

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.

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，例如乳腺癌和 小细胞肺癌，代表典型的肿瘤抑制因子。在 除了其肿瘤抑制活性之外，Rb 还能抑制细胞周期进程， 对于 DNA 损伤后诱导细胞周期停滞至关重要，并抑制 细胞死亡。 Rb 生物效应的复杂性与 多样性：结合 Rb 的蛋白质。 Rb 结合许多蛋白质，包括 E2F-1、肿瘤病毒蛋白，如 SV4O 大 T 抗原、c-Abl、MDM2 和 组蛋白脱乙酰酶。尽管 Rb 抑制细胞死亡的观察结果是 快九岁了，我们对潜在分子机制的理解 保持模糊。我们发现了保留抑制能力的 Rb 突变体 细胞周期进展，但不促进 DNA 损伤后细胞的存活。这些 研究使我们提出了 Rb 抗凋亡活性的模型 介导 Rb 在 DNA 损伤后促进细胞存活的能力 通过 Rb 的 LxCxE 结合位点。在本提案中，我们将进一步发展我们的 假设 Rb-LxCxE 相互作用在细胞中发挥重要作用 DNA损伤后的存活率。我们将检查 Rb-LxCxE 的通用性 DNA 损伤后细胞存活中的相互作用并建立其生物学 通过产生表达突变型 Rb 转基因的 Rb -I- 小鼠，具有重要意义 无法结合含有 LxCxE 基序的蛋白质。我们将表征 Rb 参与的细胞凋亡信号通路（Rb-LxCxE 相互作用）促进 细胞存活。 Rb-LxCxE相互作用与其他Rb之间的关系 Rb 存活途径中的结合蛋白也将得到阐明。这些 研究将影响我们对铷细胞生物学功能的理解 以及人类癌症。