SIGNAL-TRANSDUCTION-PATHWAY-SPECIFIC DESENSITIZATION OF EXPRESSION OFORPHAN NUCLEAR RECEPTOR TIS1

Induction of many primary-response genes by a variety of stimuli occur s in a transient manner. The precise mechanism responsible for these t ransient kinetics is not completely understood. We report here that th e orphan nuclear receptor, TIS1, which is a potent sequence-specific t ranscription factor, was transiently induced by the adrenergic agonist isoprenaline in the C2C12 skeletal-muscle cell line. Moreover, we sho wed that the rapid decline in mRNA level after peak induction was due in part to a specific desensitization of the isoprenaline-mediated ind uction pathway. Desensitization of the induction response presumably o ccurred at the level of the receptor, as agents that either bypass the adrenergic receptor or activate alternative signalling pathways were able to induce TIS1 expression in the desensitized cells. However, sti mulation by agents that directly activate intracellular enzymes also r esulted in the signal-transduction-pathway-specific desensitization of TIS1 inducibility. Our results suggest that the pathway-specific natu re of the desensitization process may be important for directing an in tegrated response to multiple physiological stimuli.