title: The transcriptional repressor ICER and cAMP-induced programmed cell death.
abstract: The cAMP pathway plays a central role in the response to hormonal signals for cell proliferation, differentiation and apoptosis. In IPC-81 leukaemia cells, activation of the cAMP pathway by prostaglandin E1 treatment, or other cAMP-elevating agents, induces apoptosis within 4-6 h. Inhibition of mRNA or protein synthesis during the first 2 h of cAMP induction protects cells from apoptosis, suggesting a requirement for early gene expression. cAMP-dependent protein kinase phosphorylates a class of nuclear factors and thereby regulates the transcription of a specific set of genes. Here we show that CREM (cAMP Responsive Element Modulator) expression is induced rapidly upon prostaglandin E1 treatment of IPC-81 cells. The induced transcripts correspond to the early product ICER (Inducible cAMP Early Repressor). ICER expression remains elevated until the burst of cell death. Protein synthesis inhibitors which prevent cAMP-induced apoptosis also block de novo ICER synthesis. Transfected IPC-81 cell lines, constitutively expressing high level of ICER are resistant to cAMP-induced cell death. In these transfected cells, cAMP fails to upregulate the ICER transcripts demonstrating that ICER exerts strongly its repressor function on CRE-containing genes. That an early expression of ICER blocks apoptosis, suggests that gene repression by endogenous ICER in IPC-81 is insufficient or occurs too late to protect cells against death. ICER transfected cells rescued from cAMP-induced apoptosis are growth arrested. It shows for the first time that CREM activation directly participates to the decision of the cell to die. ICER, by sequentially repressing distinct sets of CRE-containing genes could modulate cell fate.
authors.affiliation: INSERM U301, Centre G. Hayem, Hôpital St Louis, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Ruchaud
authors.forename: P
authors.initials: P
authors.lastname: Seité
authors.forename: N S
authors.initials: NS
authors.lastname: Foulkes
authors.forename: P
authors.initials: P
authors.lastname: Sassone-Corsi
authors.forename: M
authors.initials: M
authors.lastname: Lanotte
mesh_terms: D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000502:physiology*; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins; D014162:Transfection
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D003513:Cycloheximide; D000242:Cyclic AMP; D000527:Alprostadil