Cross-talk in signal transduction: Ras-dependent induction of cAMP-responsive transcriptional repressor ICER by nerve growth factor.
The CREM gene encodes both activators and repressors of cAMP-induced transcription. By virtue of an alternative, intronic promoter within the gene, the ICER (Inducible cAMP Early Repressor) isoform is generated. ICER acts as a dominant negative regulator and is cAMP-inducible in various neuroendocrine cells and tissues. ICER negatively autoregulates its own expression, and appears to participate in the molecular events governing oscillatory hormonal regulations. Here we report that ICER is inducible with nerve growth factor (NGF). This is the first example of cAMP-independent induction of ICER expression. Importantly, induction by NGF occurs via a subset of the CREs present in the ICER promoter which were previously shown to direct cAMP-inducibility. ICER induction correlates with a NGF-mediated phosphorylation of CREB. Both CREB phosphorylation and ICER inducibility require an intact Ras-dependent signalling pathway. We show that increased ICER levels result in the attenuation of c-fos expression. The activation of a powerful repressor of cAMP-responsive transcription by NGF, whose transduction signalling is cAMP-independent, constitutes a notable example of nuclear cross-talk and thus is likely to have relevant physiological implications.
Monaco
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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Illkirch, Strasbourg, France.
Sassone-Corsi
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D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
C495401:ADCYAP1 protein, human; C495403:Adcyap1 protein, rat; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016760:Proto-Oncogene Proteins c-fos; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP