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(Circulation Research. 2007;100:1292.)
© 2007 American Heart Association, Inc.

Molecular Medicine

CREB Mediates UTP-Directed Arterial Smooth Muscle Cell Migration and Expression of the Chemotactic Protein Osteopontin via Its Interaction with Activator Protein-1 Sites

Sandra Jalvy, Marie-Ange Renault, Laetitia Lam Shang Leen, Isabelle Belloc, Annabel Reynaud, Alain-Pierre Gadeau, Claude Desgranges

From INSERM, U441 (S.J., M.-A.R., L.L.S.L., I.B., A.R., A.-P.G., C.D.), Pessac; IFR 4 (C.D.), Pessac; and University of Bordeaux 2 (C.D.), Bordeaux, France.

Correspondence to Claude Desgranges, INSERM U441, Avenue du Haut-Leveque, F-33600 Pessac, France. E-mail claude.desgranges{at}bordeaux.inserm.fr

The transcription factor cAMP responsive element-binding protein (CREB) has been found to be involved in arterial smooth muscle cell (SMC) migration. We previously demonstrated that osteopontin (OPN) expression is a key step for UTP-mediated migration of arterial SMCs and that activator protein (AP)-1, nuclear factor B, and upstream stimulatory transcription factors are involved in this OPN expression. The present study aims to determine the role of CREB in UTP-induced migration and OPN expression in cultured SMCs. We found that CREB is activated by UTP via extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways but not by protein kinase A. Both overexpression of a dominant negative CREB and CREB small interfering RNA treatment suppressed UTP-induced OPN expression and SMC migration. Gel-shift and chromatin immunoprecipitation assays revealed that CREB binds 2 AP-1 sites (–1870 and –76) and a cAMP responsive element–like site (–1403) on the OPN promoter. Mutations of these sites showed that only the 2 AP-1 sites were required for UTP-induced OPN expression. Moreover, gel-supershift and sequential chromatin immunoprecipitation assays suggested that CREB was associated with c-Fos on the AP-1 sites of the OPN promoter. These results demonstrate that CREB participates in the induction of UTP-activated OPN expression via its binding to 2 AP-1 sites and is thus involved in UTP-mediated SMC migration.

Key Words: CREB • osteopontin • transcriptional regulation • smooth muscle cell migration

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