Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells.
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.
Cañón
Estela
E
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Cosgaya
Jose Miguel
JM
Scsucova
Sona
S
Aranda
Ana
A
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020218:Response Elements / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D014212:Tretinoin; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3