MECHANISM & REGULATION OF BCL-2 ANTIPROLIFERATIVE EFFECT

描述：（改编自研究者摘要）程控细胞 死亡或凋亡是细胞自杀的一种活跃形式， 在生理上，以确保多余或不需要的细胞被消除。 癌蛋白Bcl-2在许多情况下对抗细胞凋亡， 在恶性细胞中表达常常使化疗无效。 Bcl-2 也引起对有丝分裂原刺激的细胞的暂时不应性 增殖，但这种作用如何涉及其抗凋亡功能， 以前没有澄清过。 在这项提案中，研究人员现在证明，Bcl-2实际上 具有两个独立的功能; 它增加了细胞固有的 抵抗程序性细胞死亡，并且独立地也延迟细胞死亡。 增殖 这表明一种后生动物的策略， 具有细胞自主抗凋亡性的细胞固有地受到限制， 并认为，一个压倒性的促有丝分裂信号和/或选择性失能， Bcl-2的增殖需要Bcl-2的抗增殖作用 表达细胞 Bcl-2蛋白与细胞凋亡之间的时间相关性 磷酸化及其对细胞增殖的影响表明， 翻译后修饰可以代表一种这样的失活 机制 Bcl-2激酶启动Bcl-2抗增殖活性的失活 Bcl-2的功能可能有助于Bcl-2的继发性恶性转化 表达惰性肿瘤，如滤泡性淋巴瘤。 他们提出的研究计划旨在研究Bcl-2与细胞凋亡之间的关系。 磷酸化对其抗增殖作用的影响，以鉴定激酶 负责Bcl-2的磷酸化，并检查其在恶性肿瘤中的作用。 表达Bcl-2的惰性肿瘤的转化。 此外，希望 确定Bcl-2延迟细胞周期进程的机制。

DESCRIPTION: (adapted from the investigator's abstract) Programmed cell death, or apoptosis, is an active form of cellular suicide that functions physiologically to ensure that superfluous or unwanted cells are eliminated. The oncoprotein, Bcl-2, counters apoptosis in many instances, and when expressed in malignant cells often renders chemotherapy ineffective. Bcl-2 also provokes temporary refractoriness to mitogen stimulated cell proliferation but how this effect relates to its anti-apoptotic function was not previously clarified. In this proposal, the investigators now demonstrate that Bcl-2 in fact possesses two separate functions; ie. it increases a cell's inherent resistance against programmed cell death, and independently also delays cell proliferation. This suggests a metazoan strategy in which proliferation of cells with cell-autonomous resistance to apoptosis is inherently restricted, and argues that an overriding mitogenic signal and/or selective disabling of Bcl-2's antiproliferative effect is required for the proliferation of Bcl-2 expressor cells. The temporal correlation seen between Bcl-2's phosphorylation and its effect on cell proliferation suggests this post-translational modification may represent one such inactivation mechanism. Bcl-2 kinase initiated inactivation of Bcl-2's antiproliferative function may contribute to the secondary malignant transformations of Bcl-2 expressing indolent tumors, such as follicular lymphoma. Their proposed research program aims to examine the relation of Bcl-2's phosphorylation to its antiproliferative effect, to identify the kinase responsible for Bcl-2's phosphorylation and to examine its role in malignant transformation of Bcl-2 expressing indolent tumors. In addition, the wish to identify the mechanism by which Bcl-2 delays cell cycle progression.