: 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.
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