Regulation of cell growth and oncogenesis by BcI-2 & Bax

Bcl-2 对细胞生长和肿瘤发生的调节

• 批准号: 6769914
• 负责人: Charles Michael Knudson
• 金额: $ 26.26万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769914
• 关键词: BCL2 gene /protein; Bax gene /protein; antigen antibody reaction; apoptosis; biological signal transduction; carcinogenesis; cell cycle proteins; cell growth regulation; cell proliferation; enzyme inhibitors; gene expression; gene interaction; gene mutation; genetic models; genetically modified animals; glutathione; laboratory mouse; molecular oncology; neoplasm /cancer genetics; neoplastic growth; oxidation reduction reaction; protein kinase; protein structure function

DESCRIPTION: (provided by applicant) Bcl-2 and Bax are known regulators of cell death or apoptosis. Bcl-2 has been well studied because of its association with B Cell Lymphoma. While Bax is structurally similar to Bcl-2, it has been shown to be pro-apoptotic. Previous studies and our preliminary data have found that both Bcl-2 and Bax can either promote or inhibit tumor development. We hypothesize that these paradoxical findings for both Bcl-2 and Bax are explained by the ability of these genes to regulate cell growth as well as cell death. The studies proposed in this grant are aimed at understanding how both Bax and Bcl-2 regulate cell growth or proliferation and how this intersects with tumor development. Central to our proposal are mutant forms of Bcl-2, which retain antiapoptotic function but have lost their anti-proliferative activity. We have recently generated new transgenic mice expressing mutant Bcl-2. The oncogenic and proliferative activity of mutant Bcl-2 will be determined. Other studies will focus on the role of glutathione metabolism and REDOX regulation in BcI-2 and cell cycle control. Other studies will examine the mechanism by which Bcl-2 regulated p27 expression and function. Comparison of these cells and/or mice will allow us to dissect the signaling pathway by which Bcl-2 inhibits cell proliferation. The Specific Aims for this work are as follows: 1) Determine the oncogenic potential of mutant forms of Bcl-2 that have lost their anti-proliferative activity and determine if Bax and Bcl-2 cooperate in oncogenesis: 2) Examine how Bcl-2 regulates changes in glutathione levels and examine the importance of these changes on Bcl-2 regulation of cell proliferation 3) Determine the molecular basis for Bcl-2 regulation of p27 levels and function Blocking the anti-apoptotic activity of Bcl-2 without blocking its anti-proliferative function would have great potential in the treatment of cancer. Similarly, blocking the proliferative function of Bax without blocking its pro-apoptotic activity may be therapeutic. With these therapeutic goals in mind, we have proposed a series of studies that will provide mechanistic insight into these pathways. At the same time our animals models will provide a "proof of principle" regarding the selective regulation of these two pathways and its effect on tumor development. We believe a better understanding of the molecular basis by which Bcl-2 family members regulate proliferation and contribute to oncogenesis is very important. Our molecular studies will provide insight into the cross talk that occurs between cell death and cell proliferative pathways.

描述：（由申请人提供）Bcl-2和Bax是已知的细胞增殖调节因子。 死亡或凋亡。Bcl-2由于其与细胞凋亡的相关性而被广泛研究。 B细胞淋巴瘤。虽然Bax在结构上与Bcl-2相似，但已显示 是促凋亡的。先前的研究和我们的初步数据发现， Bcl-2和Bax都可以促进或抑制肿瘤的发展。我们 假设Bcl-2和Bax的这些矛盾的发现是 这可以通过这些基因调节细胞生长以及细胞增殖的能力来解释。 死亡这项研究的目的是为了了解这两个 Bax和Bcl-2调节细胞生长或增殖以及它们如何相互作用 肿瘤的发展。我们建议的核心是Bcl-2的突变形式， 其保留了抗凋亡功能，但失去了抗增殖功能， 活动我们最近培育了新的转基因小鼠， Bcl-2蛋白突变型Bcl-2的致癌和增殖活性将是 测定其他研究将集中在谷胱甘肽代谢的作用， BcI-2的氧化还原调节和细胞周期控制。其他研究将检查 Bcl-2调控p27表达和功能的机制。比较 这些细胞和/或小鼠将使我们能够解剖信号通路， Bcl-2抑制细胞增殖。这项工作的具体目标是， 如下：1）确定Bcl-2突变形式的致癌潜力， 已经失去了它们的抗增殖活性，并确定Bax和Bcl-2 在肿瘤发生中的合作：2）检查Bcl-2如何调节谷胱甘肽的变化 水平，并检查这些变化对细胞Bcl-2调节的重要性， 3）确定Bcl-2调节p27的分子基础 层次与功能 阻断Bcl-2的抗凋亡活性而不阻断其 抗增殖功能在治疗 癌同样，在不阻断Bax增殖功能的情况下， 其促凋亡活性可以是治疗性。随着这些治疗目标的实现， 考虑到这一点，我们提出了一系列的研究， 深入了解这些途径。与此同时，我们的动物模型将提供一个 关于这两种途径的选择性调节的"原理证明" 及其对肿瘤发展的影响。我们认为，更好地了解 Bcl-2家族成员调节增殖的分子基础， 对肿瘤发生的作用是非常重要的我们的分子研究将提供 深入了解细胞死亡和细胞凋亡之间的相互作用， 增殖途径。