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

描述：(申请人提供)Bcl2和Bax是已知的细胞调节因子 死亡或细胞凋亡。BCL-2已经被很好地研究，因为它与 B细胞淋巴瘤。虽然Bax在结构上与Bcl-2相似，但已有研究表明 是支持细胞凋亡的。之前的研究和我们的初步数据已经发现 Bcl2和Bax都可以促进或抑制肿瘤的发展。我们 假设这些关于Bcl-2和Bax的矛盾发现是 用这些基因调节细胞生长和细胞生长的能力来解释 死亡。这项拨款中提议的研究旨在了解两者如何 Bax和Bcl2调控细胞生长或增殖及其相互作用 伴随着肿瘤的发展。我们建议的核心是突变形式的Bcl-2， 它们保留了抗凋亡功能，但失去了抗增殖作用 活动。我们最近产生了新的转基因小鼠，表达突变 BCL-2。突变型Bcl-2的致癌和增殖活性将是 下定决心。其他研究将集中在谷胱甘肽代谢和 BCI-2的氧化还原调节与细胞周期调控。其他研究将检查 Bcl2调控p27表达和功能的机制。比较 这些细胞和/或老鼠的基因将使我们能够通过 哪种Bcl2抑制细胞增殖。这项工作的具体目标是 1)测定突变形式的bc l-2的致癌潜能 已经失去了抗增殖活性，并确定了Bax和Bcl2 肿瘤发生中的合作：2)研究Bcl-2如何调节谷胱甘肽的变化 水平，并检测这些变化对细胞Bcl2调控的重要性 3)确定bcl2调控p27的分子基础 层次和功能 阻断Bcl-2的抗凋亡活性而不阻断其作用 抗增殖作用在肿瘤的治疗中具有很大的潜力。 癌症。同样，在不阻断Bax的情况下，阻断Bax的增殖功能 它的促凋亡活性可能具有治疗作用。随着这些治疗目标的实现 请注意，我们已经提出了一系列研究，将提供机械论 对这些途径的洞察。同时，我们的动物模型将提供一个 关于选择性管制这两条路径的“原则证明” 以及它对肿瘤发展的影响。我们相信，更好地理解 Bcl2家族成员调控细胞增殖和凋亡的分子基础 促进肿瘤的发生是非常重要的。我们的分子研究将提供 洞察细胞死亡和细胞之间的串扰 增殖途径。

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.