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J. Biol. Chem., Vol. 279, Issue 38, 39951-39957, September 17, 2004

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Role of MAPK Phosphatase-1 (MKP-1) in Adipocyte Differentiation^*

Hiroshi Sakaue, Wataru Ogawa, Takehiro Nakamura, Toshiyuki Mori, Kyoko Nakamura, and Masato Kasuga

From the Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Both time-dependent modulation of intracellular signaling molecules and sequential induction of transcriptional regulators are essential for the differentiation of preadipocytes into adipocytes. We have now shown that the activity, but not the abundance, of p42/p44 mitogen-activated protein kinase (MAPK) is down-regulated during adipocyte differentiation. This decrease in p42/p44 MAPK activity does not appear to be a direct effect of hormonal inducers of differentiation but rather represents a characteristic event of adipocyte differentiation that is achieved through a persistent change in intracellular signaling. Although the phosphorylation or abundance of MEK, an upstream kinase for p42/p44 MAPK, was not altered during differentiation, the abundance of MAPK phosphatase-1 (MKP-1), a negative regulator of p42/p44 MAPK, was increased with a time course similar to that of the down-regulation of p42/p44 MAPK activity. Ectopic expression of MKP-1 in preadipocytes reduced and depletion of endogenous MKP-1 in mature adipocytes increased the activity of p42/p44 MAPK. Prevention of the up-regulation of MKP-1 abundance in preadipocytes by expression of Mkp-1 antisense RNA resulted in persistence of p42/p44 MAPK activation and blocked differentiation, effects that were reversed by the MEK inhibitor PD98059. These results suggest that MKP-1 plays an essential role in adipocyte differentiation through down-regulation of p42/p44 MAPK activity.

Received for publication, July 1, 2004

^* This work was supported by grants from Yamanouchi Foundation for Research on Metabolic Disorders and the Suzuken Memorial Foundation (to H. S.), grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. K. and W. O.), a grant for the 21st Century COE Program "Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model" from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. K.), and a grant for the Cooperative Link of Unique Science and Technology for Economy Revitalization from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. K.). 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.

To whom correspondence should be addressed: Dept. of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel.: 81-78-382-5861; Fax: 81-78-382-2080; E-mail: ogawa{at}med.kobe-u.ac.jp.

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