title: 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.
authors.affiliation: Max Delbrück Zentrum, Berlin, Germany.
authors.forename: T G
authors.initials: TG
authors.lastname: Darby
authors.forename: J D
authors.initials: JD
authors.lastname: Meissner
authors.forename: A
authors.initials: A
authors.lastname: Rühlmann
authors.forename: W H
authors.initials: WH
authors.lastname: Mueller
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheibe
mesh_terms: D002454:Cell Differentiation; D002455:Cell Division; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005622:Friend murine leukemia virus; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D000090063:Proto-Oncogene Mas; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; C000607071:RARA protein, human; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; D014212:Tretinoin; D004247:DNA