TRANSFORMATION OF CELLS BY THE V-REL ONCOGENE

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The Re1/-NF-KB family of transcription factors controls the growth and differentiation of vertebrate lymphoid cells, and mutant re1 genes have been associated with a number of lymphoid cancers in animals and humans. This work has had a continuing focus on understanding the cellular and molecular mechanisms by which Re1 transcription factors affect cell growth. In particular, the mechanism by which the v-Re1 oncoprotein of the avian Rev-T retrovirus induces malignant transformation and immortalization of avian lymphoid cells, and by which v-Re1 is toxic in mammalian cells will be investigated. Specifically, the following aims will be accomplished: a chicken re1B cDNA will be isolated and the ability of Re1B to interact with v-Re1 will be assessed; cDNAs encoding proteins that can interact with and modulate the activities to C-terminal sequences of v-Re1 will be identified and characterized; the effect of anti-apoptosis proteins on immortalization of cells by v-Re1 will be determined; the ability of v-Re1 mutants to induce toxicity in mammalian fibroblasts will be determined; as says will be developed to study the malignant transforming potential of other avian and mammalian Re1 proteins in avian and mammalian cells; and cellular genes whose expression is commonly altered in Re1-transformed cells will be identified. Furthermore, the mechanism by which certain Del proteins activate transcription will be investigated by determining what types of general transcription factors (such as transcriptional adapters) are needed for transcriptional activation by v-Re1, c-Re1, Re1A, and p85, an oncogenic form of NF-KB p100 found in HUT78 human leukemia cells. Together, these experiments will serve as models for understanding the molecular mechanisms underlying the development of a subset of human lymphoid malignancies.