AN FK506-SENSITIVE TRANSPORTER SELECTIVELY DECREASES INTRACELLULAR LEVELS AND POTENCY OF STEROID-HORMONES

Steroid hormones bind and activate intracellular receptors that are li gand-regulated transcription factors. Mammalian steroid receptors can confer hormone-dependent transcriptional enhancement when expressed in yeast, thereby enabling the genetic identification of nonreceptor pro teins that function in the hormone signal transduction pathway. Pdr5p (Lem1/Sts/Ydr1p), a yeast ATP-binding cassette transporter, selectivel y decreases the intracellular levels of particular steroid hormones, i ndicating that active processes can affect the passage of steroids acr oss biological membranes. In yeast, the immunosuppressive drug FK506 i nhibited Pdr5p, thereby potentiating activation of the glucocorticoid receptor by dexamethasone, a Ligand that is exported by Pdr5p. In mamm alian L929 cells but not in HeLa cells, FK506 potentiated dexamethason e responsiveness and increased dexamethasone accumulation, without alt ering the hormone-binding properties of the glucocorticoid receptor. W e suggest that an FK506-sensitive transporter in L929 cells selectivel y decreases intracellular hormone levels and, consequently, the potenc y 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.