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Activation of Extracellular Signal-Regulated Kinases and CREB/ATF-1 Mediate the Expression of CCAAT/Enhancer Binding Proteins ß and - in Preadipocytes

Institute of Signaling, Development Biology and Cancer Research (N.B., B.W.P., F.M., P.V., B.W., P.S.-M., J.A., G.A., C.D.), UMR 6543 Centre Nationale de la Recherche Scientifique, Centre de Biochimie 06108 Nice Cedex 2, France; Centre for Genome Research (J.N.), University of Edinburgh, United Kingdom; Department of Hematology (K.S., A.Y.), Research Institute, International Medical Centre of Japan, Tokyo 162-8655, Japan; and Department of Pharmacology (S.N.), Kyoto University, Kyoto 606-8501, Japan

Address all correspondence and requests for reprints to: Dr. Christian Dani, Centre de Biochimie (UMR 6543 CNRS), UNSA, Faculté des Sciences, Parc Valrose, 06108 Nice cedex 2, France. E-mail: dani{at}unice.fr

The essential role of CCAAT/enhancer binding proteins (C/EBPs) ß and for adipocyte differentiation has been clearly established. In preadipocytes, their expression is up-regulated by the activation of leukemia inhibitory factor receptor (LIF-R) and prostacyclin receptor (IP-R) via the extracellular signal-regulated kinase (ERK) pathway and cAMP production, respectively. However, the molecular mechanisms by which LIF and prostacyclin-induced signals are propagated to the nucleus and the transcription factors mediating ERK and cAMP-induced C/EBP gene expression were unknown. Here we report that both pathways share cAMP responsive element binding protein/activation transcription factor 1 (CREB/ATF-1) as common downstream effectors. LIF-R and IP-R activation induced binding of CREB and/or ATF-1 to C/EBP promoters and CREB-dependent transcription. Expression of dominant negative forms of CREB dramatically reduced the LIF- and prostacyclin-stimulated C/EBP ß and C/EBP expression. Upon stimulation of the IP-R, the ERK pathway was activated in a PKA-dependent manner. ERK activation by the PKA pathway was not required for CREB/ATF-1 phosphorylation but rather was necessary for CREB-dependent up-regulation of C/EBPs expression. Our findings suggest that ERK activation is required for CREB transcriptional activity, possibly by recruitment of a coactivator.

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