Mechanism of cell cycle and oncogenesis by c Rel

描述(申请人提供)：c-rel原癌基因， 核因子-kappaB/Rel转录因子家族在转录调控中起重要作用 淋巴细胞的增殖和存活过程。C-Rel Has的调节失调 已发现与人类弥漫性大细胞的高发病率有关 淋巴瘤。此外，v-rel在转基因小鼠中的过度表达导致 T细胞白血病和淋巴瘤的发生。然而，通过这些机制 C-Ret对细胞周期的调控和肿瘤的发生仍知之甚少。 我们假设Rel的致癌潜力与其能力有关 诱导参与细胞周期和生存的基因，基于我们的 初步研究：(1)REL(-/-)淋巴细胞有严重的增殖缺陷 对抗原性和有丝分裂刺激的反应。(2)细胞因子缺乏 产生(例如T细胞中的IL-2，B细胞中的IL-6)的部分原因是 Rel(-/-)淋巴细胞增殖缺陷。(3)Rel(-/-)B细胞 Cyclin D2、D3和E诱导减少，CDK激酶活性受损，以及 降低E2F的表达。我们认为c-Rel与细胞因子具有协同作用。 几种细胞周期事件的调节：包括细胞周期蛋白D的诱导， E2F4的表达和CDK激酶的激活。以下目标将是 已调查： 目的1：确定c-Rel直接调控哪些细胞周期基因 和/或细胞因子。目标2：确定是否有任何细胞周期进展事件 受c-Ret和/或细胞因子转录后调控。目标3：实现 确定c-rel调控的生存和细胞周期基因是否可以协同作用 在体外和体内诱导细胞转化。 我们的研究将促进对淋巴细胞周期进程的理解 以及肿瘤发生的机制，并最终促进 确定免疫缺陷治疗的潜在靶点， 淋巴增生症、慢性炎症和/或自身免疫。

DESCRIPTION (Provided by the Applicant): C-Rel proto-oncogene, a member of the NF-kappaB/Rel transcription factor family, plays a crucial role in regulating lymphocyte proliferation and survival processes. Dysregulation of c-Rel has been found to associate with high incidence of human diffuse large cell lymphoma. Furthermore, v-Rel over-expression in transgenic mice lead to the development of T cell leukemia and lymphomas. However, the mechanisms by which c-Ret modulates cell cycle and oncogenesis are still poorly understood. We hypothesize that Rel's oncogenic potential is linked to its ability to induce genes that are involved in cell cycle and survival, based on our preliminary studies: (1) Rel(-/-) lymphocytes have severe proliferative defects in response to antigenic and mitogenic stimuli. (2) The lack of cytokine production (e.g. IL-2 in T cells, IL-6 in B-cells) partly accounts for the proliferation defects of Rel(-/-) lymphocytes. (3) Rel(-/-) B-cells have reduced cyclin D2, D3, and E induction, impaired CDK kinase activation, and reduced E2F expression. We propose that c-Rel synergizes with cytokines in the regulation of several cell cycle events: including the induction of cyclin Ds, expression of E2F4, and activation of CDK kinases. The following aims will be investigated: Aim 1: To determine which cell cycle genes are directly regulated by c-Rel and/or cytokines. Aim 2: To determine whether any cell cycle progression events are regulated post-transcriptionally by c-Ret and/or cytokine. Aim 3: To determine whether c-Rel-regulated survival and cell cycle genes can cooperate to induce cell transformation in vitro and in vivo. Our studies will advance the understanding of lymphocyte cell cycle progression as well as the mechanisms of oncogenesis and eventually facilitate the identification of potential targets for the treatment of immunodeficiency, lymphomagenesis, chronic inflammation, and/or autoimmunity.