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Originally published In Press as doi:10.1074/jbc.M203870200 on May 8, 2002

J. Biol. Chem., Vol. 277, Issue 29, 26335-26339, July 19, 2002
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Deregulated MAPK Activity Prevents Adipocyte Differentiation of Fibroblasts Lacking the Retinoblastoma Protein*

Jacob B. HansenDagger §, Rasmus K. PetersenDagger ||, Claus JørgensenDagger , and Karsten KristiansenDagger **

From the Dagger  Department of Biochemistry and Molecular Biology, Center for Experimental BioInformatics, University of Southern Denmark, DK-5230 Odense M, Denmark and || Rheoscience A/S, DK-2610 Rødovre, Denmark

A functional retinoblastoma protein (pRB) is required for adipose conversion of preadipocyte cell lines and primary mouse embryo fibroblasts (MEFs) in response to treatment with standard adipogenic inducers. Interestingly, lack of functional pRB in MEFs was recently linked to elevated Ras activity. Ras-dependent signaling plays a significant, although incompletely understood, role in adipocyte differentiation, because activated Ras has been reported to either promote or inhibit adipogenesis depending on the cellular context. In various cell types activation of Ras leads to activation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (PKB)/Akt, which exert opposing effects on adipogenesis, with ERK1/2 inhibiting and PKB/Akt promoting terminal differentiation. Here we report that the levels of activated ERK1/2 and PKB/Akt are significantly increased in pRB-deficient MEFs both before and after the addition of adipogenic inducers. Consistently, we detected higher levels of activated Ras in MEFs lacking pRB. Suppression of ERK1/2 activation by the MEK inhibitor UO126 restored the ability of pRB-deficient MEFs to undergo adipocyte differentiation, as manifested by expression of adipocyte marker genes and lipid accumulation. Furthermore and reflecting the elevated levels of activated PKB/Akt in the pRB-deficient MEFs, differentiation proceeded in an insulin-independent manner. In conclusion, we suggest that pRB plays a pivotal role in adipogenesis by suppressing MAPK activity.

* This work was supported by the Danish Biotechnology Program, the Danish Cancer Society, the Danish Natural Science Research Council, and the Novo Nordisk Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: The Netherlands Cancer Institute, Division of Molecular Biology, Plesmanlaan 121, NL-1066 CX Amsterdam, The Netherlands.

These authors contributed equally to this work.

** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. Tel.: 45-65502408; Fax: 45-65502467; E-mail: kak@bmb.sdu.dk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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