Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1.

Abstract

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 (RAR alpha) 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, RAR alpha is able to repress Fli-1-mediated transcriptional activation. Transfection analysis of RAR alpha and Fli-1 mutants in cultured cells demonstrate that the DNA binding domain of RAR alpha and the N-terminal region of Fli-1 are required for repression. Gel retardation analysis demonstrates that RAR alpha cannot bind to the Fli-1 binding site in the E74 promoter and the expression of Fli-1 does not affect RAR alpha binding to DNA. Furthermore, the data suggest an indirect interaction between Fli-1 and RAR alpha 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 RA-induced differentiation 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.