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 post-translational 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.
Folco
E J
EJ
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Koren
G
G
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D051786:Cyclic AMP Response Element Modulator; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D007473:Ion Channels / Q000096:biosynthesis; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D012097:Repressor Proteins; D014158:Transcription, Genetic / Q000187:drug effects; D014452:Ubiquitins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007473:Ion Channels; D007976:Leupeptins; D009097:Multienzyme Complexes; D012097:Repressor Proteins; D014452:Ubiquitins; C089487:acetyl-leucinyl-leucinyl-methional; C067713:lactacystin; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine