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J. Biol. Chem. 280 (42): 35081-35084

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulation of the Transcriptional Activity of c-Fos by ERK


Paula Monje1, Javier Hernández-Losa2, Ruth J. Lyons, Maria D. Castellone, , and J. Silvio Gutkind3

Oral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institutes of Health, DHHS, Bethesda, Maryland 20892-4330

Abstract: The activation of the activating protein-1 (AP-1) family of transcription factors, including c-Fos and c-Jun family members, is one of the earliest nuclear events induced by growth factors that stimulate extracellular signal-regulated kinases (ERKs). In the case of c-Fos, the activation of ERK leads to an increased expression of c-fos mRNA. In turn, we have recently shown that ERK phosphorylates multiple residues within the carboxylterminal transactivation domain (TAD) of c-Fos, thus resulting in its increased transcriptional activity. However, how ERK-dependent phosphorylation regulates c-Fos function is still poorly understood. In this regard, it has been recently observed that the prolyl isomerase Pin1 can interact with proteins phosphorylated on serine or threonine residues that precede prolines (pS/T-P), such as the transcription factors p53 and c-Jun, thereby controlling their activity by promoting the cis-trans isomerization of these pS/T-P bonds. Here, we found that Pin1 binds c-Fos through specific pS/T-P sites within the c-Fos TAD, and that this interaction results in an enhanced transcriptional response of c-Fos to polypeptide growth factors that stimulate ERK. Our findings suggest that c-Fos represents a novel target for the isomerizing activity of Pin1 and support a role for Pin1 in the mechanism by which c-Jun and c-Fos can cooperate to regulate AP-1-dependent gene transcription upon phosphorylation by mitogen-activated kinase (MAPK) family members.

Received for publication August 15, 2005.

* This work was supported by the Intramural Research Program of the National Institutes of Health, NIDCR. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Current address: The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL 33136.

2 Current address: Molecular Pathology, Hospital Vall d'Hebron, 08035 Barcelona, Spain.

3 To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, NIDCR, NIH, 30 Convent Dr., Bldg. 30, Rm. 211, Bethesda, MD 20892-4340. Tel.: 301-496-6259; Fax: 301-402-0823; E-mail: sg39v{at}

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