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Transcriptional induction by steroid receptors is coupled to cellular signal transduction pathways although, in general, the mechanisms governing these events are not well defined. Using TATA-binding protein (TBP) specificity mutants that recognize a TGTA box, we show that yeast TBP expressed in mammalian cells can support steroid-mediated gene induction to a similar degree as human TBP, however yeast TBP does not support the 8-Bromo-cAMP-mediated potentiation of glucocorticoid receptor (GR)-dependent transactivation. Chimeras between yeast and human TBP reveal that it is the non-conserved N-terminus of TBP that governs the potentiation of GR action. While the conserved core of TBP is sufficient for TATA-element binding and preinitiation complex formation, the role of the N-terminus has remained elusive. Our results suggest a role of the N-terminus of human TBP in coupling cell signaling events to steroid-mediated transcription, thereby establishing one of the few described functional roles of this polypeptide domain in a physiological process.