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.