PHYSICAL INTERACTION BETWEEN RETINOIC ACID RECEPTOR AND THE ONCOPROTEIN MYB INHIBITS RETINOIC ACID-DEPENDENT TRANSACTIVATION

The c-myb protooncogene is predominantly expressed in hematopoietic ce lls and plays a vital role in hematopoiesis, Retinoic acid (RA) is abl e to induce differentiation of several hematopoietic cells. This diffe rentiation is linked to decreased c-myb expression, suggesting that re tinoid receptors (RAR/RXR) may down-regulate c-myb gene expression. Fu rthermore, recent data indicate that RAR inhibits the function of the Myb protein itself. In addition, the Myb-Ets oncogenic fusion protein has been shown to inhibit transcriptional activation by RAR and thyroi d hormone receptor, Myb-Ets also antagonizes the biological response o f erythrocytic progenitor cells to RA and thyroid hormone. This prompt ed us to investigate a possible cross talk between RAR and Myb, Were, we demonstrate that RA inhibits the expression of the endogenous Myb t arget gene tom-1. Conversely, Myb functions as a potent inhibitor of R A-induced biological responses. Functional analysis of Myb mutants in transfection studies revealed that the Myb DNA-binding domain (DBD) is necessary for repression whereas the transactivation domain is dispen sable. Furthermore, we show that v-Myb and RAR interact in vitro and i n vivo. This interaction requires the DBD of RAR, In contrast, glutath ione S-transferase-pulldown assays with v-Myb mutants indicate that th e DBD and the C terminus of Myb directly interact with RAR, Our result s suggest that the physical interaction between Myb and RAR may play a role in the regulation of hematopoietic gene expression.