SUPPRESSION OF V MYB TRANSFORMATION BY RAR AND RXR

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DESCRIPTION The overall goal of this proposal is to understand the mechanism by which the retinoic acid receptor-a suppresses transformation by the v-Myb oncoprotein. v-Myb transforms monoblasts, macrophage precursors which are blocked in their ability to differentiate. However, the introduction of exogenous RAR-a into the v- Myb-transformed BM2 cell line permits macrophage differentiation in response to retinoic acid, despite the continued presence of the v-Myb protein. Because RAR generally functions as a heterodimer with an RXR protein, the role of RXR proteins in this system is a major focus for the next three-year period. The specific aims for understanding the mechanism by which RAR-a suppresses transformation by v- Myb are the following: 1) Preparation of RXR-a and RXR-a-specific monoclonal antibodies; 2) Preparation and analysis of RXR-a and RXR-a-expressing BM2 cells; 3) Determination of the effect of RAR/RXR on transcriptional activation by v-Myb, and conversely, determination of the effect of v-Myb on transcriptional regulation by RAR/RXR; 4) Analysis of the effect of RAR/RXR upon DNA-binding by v-Myb and vice versa; 5) Analysis of the effect of RAR and RXR upon TPA-induced differentiation of BM2 cells; and 6) Identification of genes which are differentially expressed in Ra treated BM2 and BM2-RAR cells.