FUNCTIONAL INTERFERENCE BETWEEN RETINOIC ACID OR STEROID-HORMONE RECEPTORS AND THE ONCOPROTEIN FLI-1

The Fli-1 protein is a member of the ets proto-oncogene family, whose overexpression is a consequence of Friend murine leukemia virus (F-MuL V) integration in Friend erythroleukemic cells. We present evidence th at Fli-1 and the retinoic acid receptor (RAR alpha) can reciprocally r epress one another's transcriptional activation. Overexpression of Fli -1 inhibits the retinoic acid-induced activation of genes carrying a f unctional retinoic acid response element (RARE), Conversely, RAR alpha is able to repress Fli-1-mediated transcriptional activation. Transfe ction analysis of RAR alpha and Fli-1 mutants in cultured cells demons trate that the DNA binding domain of RAR alpha and the N-terminal regi on of Fli-1 are required for repression, Gel retardation analysis demo nstrates that RAR alpha cannot bind to the Fli-1 binding site in the E 74 promoter and the expression of Fli-1 does not affect RAR alpha bind ing to DIVA, Furthermore, the data suggest an indirect interaction bet ween Fli-1 and RAR alpha mediated by a 'bridging' factor(s) present in nuclear extracts from RM10 erythroleukemia cells, Fli-1 also interfer es with the action of receptors for thyroid or glucocorticoid hormone in several hematopoietic cell lines, The RA-induced differentiation an d decrease of cell proliferation was blocked in myeloblastic leukemia HL-60 cells overexpressing the N-terminal region of Fli-1 at physiolog ical concentrations of RA. These data suggest that accumulation of Fli -1 can oppose the transcriptional activity of hormone receptors in hem atopoietic cells.