title: An FK506-sensitive transporter selectively decreases intracellular levels and potency of steroid hormones.
abstract: Steroid hormones bind and activate intracellular receptors that are ligand-regulated transcription factors. Mammalian steroid receptors can confer hormone-dependent transcriptional enhancement when expressed in yeast, thereby enabling the genetic identification of nonreceptor proteins that function in the hormone signal transduction pathway. Pdr5p (Lem1/Sts1/Ydr1p), a yeast ATP-binding cassette transporter, selectively decreases the intracellular levels of particular steroid hormones, indicating that active processes can affect the passage of steroids across biological membranes. In yeast, the immunosuppressive drug FK506 inhibited Pdr5p, thereby potentiating activation of the glucocorticoid receptor by dexamethasone, a ligand that is exported by Pdr5p. In mammalian L929 cells but not in HeLa cells, FK506 potentiated dexamethasone responsiveness and increased dexamethasone accumulation, without altering the hormone-binding properties of the glucocorticoid receptor. We suggest that an FK506-sensitive transporter in L929 cells selectively decreases intracellular hormone levels and, consequently, the potency of particular steroids. Thus, steroid transporters may modulate, in a cell-specific manner, an initial step in signaling, the availability of hormone to the receptor.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143-0448, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kralli
authors.forename: K R
authors.initials: KR
authors.lastname: Yamamoto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D003900:Desoxycorticosterone / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D005656:Fungal Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007739:L Cells; D008322:Mammals; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology*; D014162:Transfection; D014222:Triamcinolone Acetonide / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D005656:Fungal Proteins; D008565:Membrane Proteins; C092438:PDR5 protein, S cerevisiae; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D003900:Desoxycorticosterone; D003907:Dexamethasone; D014222:Triamcinolone Acetonide; D016559:Tacrolimus