Degradation of the inducible cAMP early repressor (ICER) by the ubiquitin-proteasome pathway

The inducible cAMP early repressor (ICER) is a powerful transcriptional inhibitor that plays an important role in the regulation of the cAMP-dependent transcriptional response in the neuroendocrine system. ICER activity is primarily determined by its intracellular concentration, rather than by posttranslational modifications, such as phosphorylation. We investigated the mechanisms that regulate the levels of ICER transcript and polypeptides in cardiocytes, myogenic (C2C12) and pituitary-derived (GH3) cell lines. We show that in primary cardiocytes and GH3 cells ICER was inducible by cAMP but not by membrane depolarization. Moreover, lactacystin, a specific proteasome inhibitor, decreased the rate of ICER degradation. This effect was associated with the accumulation of ICER-ubiquitin conjugates. We conclude that the intracellular levels of ICER are controlled by the ubiquitin-proteasome pathway for protein breakdown.