Activation of extracellular signal-regulated kinases and CREB/ATF-1 mediate the expression of CCAAT/enhancer binding proteins beta and -delta in preadipocytes

The essential role of CCAAT/enhancer binding proteins (C/EBPs) beta and del ta for adipocyte differentiation has been clearly established. In preadipoc ytes, their expression is up-regulated by the activation of leukemia inhibi tory factor receptor (LIF-R) and prostacyclin receptor (IP-R) via the extra cellular signal-regulated kinase (ERK) pathway and cAMP production, respect ively. However, the molecular mechanisms by which LIF and prostacyclin-indu ced signals are propagated to the nucleus and the transcription factors med iating ERK and cAMP-induced C/EBP gene expression were unknown. Here we rep ort that both pathways share cAMP responsive element binding protein/activa tion transcription factor 1 (CREB/ATF-1) as common downstream effectors. LI F-R and IP-R activation induced binding of CREB and/or ATF-1 to C/EBP promo ters and CREB-dependent transcription. Expression of dominant negative form s of CREB dramatically reduced the LIF- and prostacyclin-stimulated C/EBP b eta and C/EBP delta expression. Upon stimulation of the IP-R, the ERK pathw ay was activated in a PKA-dependent manner, ERK activation by the PKA pathw ay was not required for CREB/ATF-1 phosphorylation but rather was necessary for CREB-dependent up-regulation of C/EBPs expression. Our findings sugges t that ERK activation is required for CREB transcriptional activity, possib ly by recruitment of a coactivator.