RB AS A REGULATOR OF PROSTATE TUMORIGENESIS

RB 作为前列腺肿瘤发生的调节剂

• 批准号: 6203364
• 负责人: MARK L DAY
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-09 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203364
• 关键词: Adenoviridae; animal genetic material tag; apoptosis; athymic mouse; carcinogenesis; cell line; connective tissue cells; epithelium; gene deletion mutation; gene therapy; genetic transduction; laboratory mouse; laboratory rat; loss of heterozygosity; male; molecular oncology; neoplasm /cancer genetics; neoplastic process; nonhuman therapy evaluation; prostate neoplasms; retinoblastoma protein; tissue mosaicism; transfection /expression vector; tumor suppressor genes

As a regulatory inhibitor of cell cycle, the retinoblastoma protein (Rb) is central to a tumor suppressive pathway that is frequently disrupted in human cancer. LOH of the retinoblastoma gene (Rb) is one of the most common mutations associated with prostate cancer and through much of the molecular function of Rb is known, it's role in the pathobiology of prostate cancer has not been investigated. Some of the mutation events that occur during the prostate tumorigenesis involve alterations to apoptotic programs present in normal prostate epithelium. Therefore, the ability of prostate epithelial cells to circumvent apoptosis may be important in prostate tumorigenesis. During the first two years of our SPORE-funded research, we develop two cell culture models with which we have demonstrated that apoptosis of prostate epithelial cells is uniquely regulated through the Rb cell cycle control pathway. Additionally, we have shown that activation of the Rb pathway occurs in the rat prostate gland during castration-induced apoptosis. Based on these studies, we hypothesize that the loss of Rb function may facilitate tumor formation by inactivating an Rb-dependent apoptotic mechanism. To elucidate the role of Rb in prostate tumorigenesis we have developed a unique in vivo model system with which to study homozygous deletion of the RB gene in mouse prostate epithelium. We will also determine the efficacy of an Rb adenoviral construct to induce apoptosis of prostate cancer cells. We will pursue these goals by addressing the following specific aims. Specific Aim 1. To investigate the tumorigenic effects of Rb deletion over time, we will analyze Rb-/-E in the TR system for tumor formation over a period of one year. Specific Aim 2. To investigate the tumorigenic effect of Rb deletion in the TR system, we will analyze Rb-/- E in the presence of tumor stroma. Specific Aim 3. To determine if constitutively active Rb, delivered with the adenovirus system will induce apoptosis of prostate cancer cells. We anticipate that the results from this study would be the first to identify a pathobiological role for Rb in prostate tumorigenesis and the first to define a critical component of an androgen-regulated apoptotic program in prostate epithelium in vivo.

作为细胞周期的调节抑制剂，视网膜细胞瘤蛋白（RB） 是经常被破坏的肿瘤抑制途径的核心 人类癌。视网膜母细胞瘤基因（RB）的LOH是最多的。 与前列腺癌和大部分相关的常见突变 RB的分子功能是已知的，它在病理学中的作用 尚未研究前列腺癌。一些突变事件 在前列腺肿瘤发生期间发生的涉及 正常前列腺上皮中存在的凋亡程序。因此， 前列腺上皮细胞规避凋亡的能力可能是 在前列腺肿瘤发生中很重要。在我们的前两年 孢子资助的研究，我们开发了两个细胞培养模型 已经证明前列腺上皮细胞的凋亡是独特的 通过RB细胞周期控制途径进行调节。另外，我们还有 表明RB途径的激活发生在大鼠前列腺中 在cast割引起的凋亡过程中。基于这些研究，我们 假设RB功能的丧失可能促进通过 失活Rb依赖性凋亡机制。阐明 RB在前列腺肿瘤发生中，我们开发了一个独特的体内模型 研究小鼠Rb基因纯合缺失的系统 前列腺上皮。我们还将确定RB的功效 腺病毒构建体可诱导前列腺癌细胞凋亡。我们将 通过解决以下特定目标来实现这些目标。 特定目的1。研究RB缺失的致瘤作用 时间，我们将在TR系统中分析rb - / - e的肿瘤形成 一年。 具体目的2。研究RB缺失的致瘤作用 TR系统，我们将在存在肿瘤基质的情况下分析Rb - / - E。 特定目的3。确定与组成性活跃的RB是否交付 腺病毒系统将诱导前列腺癌细胞凋亡。 我们预计这项研究的结果将是第一个 确定RB在前列腺肿瘤发生中的病理生物学作用和 首先定义雄激素调节的凋亡的关键成分 体内前列腺上皮的程序。