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 t ranscription. By virtue of an alternative, intronic promoter within th e 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 autoregulate s its own expression, and appears to participate in the molecular even ts governing oscillatory hormonal regulations. Here we report that ICE R is inducible with nerve growth factor (NGF). This is the first examp le of cAMP-independent induction of ICER expression. Importantly, indu ction by NGF occurs via a subset of the CREs present in the ICER promo ter which were previously shown to direct cAMP-inducibility. ICER indu ction correlates with a NGF-mediated phosphorylation of CREB. Both CRE B phosphorylation and ICER inducibility require an intact Ras-dependen t signalling pathway. We show that increased ICER levels result in the attenuation of c-fos expression. The activation of a powerful repress or of cAMP-responsive transcription by NGF, whose transduction signall ing is cAMP-independent, constitutes a notable example of nuclear cros s-talk and thus is likely to have relevant physiological implications.