The Fli-1 protein is a member of the ets proto-oncogene family, whose overexpression is a consequence of Friend murine leukemia virus (F-MuLV) integration in Friend erythroleukemic cells. We present evidence that Fli-1 and the retinoic acid receptor (RARa) can reciprocally repress one another's transcriptional activation. Overexpression of Fli-1 inhibits the retinoic acid-induced activation of genes carrying a functional retinoic acid response element (RARE). Conversely, RARa is able to repress Fli-1-mediated transcriptional activation. Transfection analysis of RARa and Fli-1 mutants in cultured cells demonstrate that the DNA binding domain of RARa and the N-terminal region of Fli-1 are required for repression. Gel retardation analysis demonstrates that RARa cannot bind to the Fli-1 binding site in the E74 promoter and the expression of Fli-1 does not aect RARa binding to DNA. Furthermore, the data suggest an indirect interaction between Fli-1 and RARa mediated by a`bridging' factor(s) present in nuclear extracts from RM10 erythroleukemia cells. Fli-1 also interferes with the action of receptors for thyroid or glucocorticoid hormone in several hematopoietic cell lines. The RAinduced dierentiation and decrease of cell proliferation was blocked in myeloblastic leukemia HL-60 cells overexpressing the N-terminal region of Fli-1 at physiological concentrations of RA. These data suggest that accumulation of Fli-1 can oppose the transcriptional activity of hormone receptors in hematopoietic cells.
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