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MBC in Press, published online ahead of print September 15, 2004
Mol. Biol. Cell 10.1091/mbc.E04-05-0439

A more recent version of this article appeared on December 1, 2004
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Submitted on May 31, 2004
Revised on July 28, 2004
Accepted on September 3, 2004

Rapid Effects of Retinoic Acid on CREB and ERK Phosphorylation in Neuronal Cells

Estela Cañón, Jose Miguel Cosgaya, Sona Scsucova, and Ana Aranda*

Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain

Monitoring Editor: Keith Yamamoto

Retinoic acid (RA) is a potent regulator of neuronal cell differentiation. RA normally activates gene expression by binding to nuclear receptors that interact with response elements (RAREs) in regulatory regions of target genes. We show here that in PC12 cell subclones in which the retinoid causes neurite extension, RA induces a rapid and sustained phosphorylation of CREB (cyclic AMP response element binding protein), compatible with a nongenomic effect. RA also causes a rapid increase of CREB phosphorylation in primary cultures of cerebrocortical cells and of dorsal root ganglia neurons from rat embryos. RA-mediated phosphorylation of CREB leads to a direct stimulation of CREB-dependent transcriptional activity, and to activation of the expression of genes such as c-fos, which do not contain RAREs but contain cAMP response elements (CREs) in their promoters. CREB is a major target of extracellular signal regulated kinase ERK1/2 signaling in neuronal cells, and we demonstrate here that RA induces an early stimulation of ERK1/2, which is required both for CREB phosphorylation and transcriptional activity. These results demonstrate that RA, by a nongenomic mechanism, stimulates signaling pathways that lead to phosphorylation of transcription factors, which in turn activate the transcription of genes involved in neuronal differentiation.

*Corresponding author. E-mail: aaranda{at}iib.uam.es






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