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Molecular and Cellular Biology, July 2005, p. 5466-5479, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5466-5479.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Selective Activation of Mitogen-Activated Protein (MAP) Kinase Kinase 3 and p38{alpha} MAP Kinase Is Essential for Cyclic AMP-Dependent UCP1 Expression in Adipocytes

Jacques Robidoux,1,3 Wenhong Cao,2,3 Hui Quan,3 Kiefer W. Daniel,1,3 Fatiha Moukdar,3 Xu Bai,1 Lisa M. Floering,1,3 and Sheila Collins1,2,3*

Department of Psychiatry and Behavioral Sciences,1 Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710,2 Endocrine Biology Program, Division of Biological Sciences, CIIT Centers for Health Research, Research Triangle Park, North Carolina 277093

Received 25 November 2004/ Returned for modification 21 December 2004/ Accepted 1 April 2005

The sympathetic nervous system regulates the activity and expression of uncoupling protein 1 (UCP1) through the three ß-adrenergic receptor subtypes and their ability to raise intracellular cyclic AMP (cAMP) levels. Unexpectedly, we recently discovered that the cAMP-dependent regulation of multiple genes in brown adipocytes, including Ucp1, occurred through the p38 mitogen-activated protein kinases (MAPK) (W. Cao, K. W. Daniel, J. Robidoux, P. Puigserver, A. V. Medvedev, X. Bai, L. M. Floering, B. M. Spiegelman, and S. Collins, Mol. Cell. Biol. 24:3057-3067, 2004). However, no well-defined pathway linking cAMP accumulation or cAMP-dependent protein kinase (PKA) to p38 MAPK has been described. Therefore, in the present study using both in vivo and in vitro models, we have initiated a retrograde approach to define the required components, beginning with the p38 MAPK isoforms themselves and the MAP kinase kinase(s) that regulates them. Our strategy included ectopic expression of wild-type and mutant kinases as well as targeted inhibition of gene expression using small interfering RNA. The results indicate that the ß-adrenergic receptors and PKA lead to a highly selective activation of the p38{alpha} isoform of MAPK, which in turn promotes Ucp1 gene transcription. In addition, this specific activation of p38{alpha} relies solely on the presence of MAP kinase kinase 3, despite the expression in brown fat of MKK3, -4, and -6. Finally, of the three scaffold proteins of the JIP family expressed in brown adipocytes, only JIP2 coimmunoprecipitates p38{alpha} MAPK and MKK3. Therefore, in the brown adipocyte the recently described scaffold protein JIP2 assembles the required factors MKK3 and p38{alpha} MAPK linking PKA to the control of thermogenic gene expression.

* Corresponding author. Mailing address: CIIT Centers for Health Research, 6 Davis Drive, Box 12137, Research Triangle Park, NC 27709. Phone: (919) 558-1378. Fax: (919) 558-1305. E-mail: scollins{at}ciit.org.

Molecular and Cellular Biology, July 2005, p. 5466-5479, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5466-5479.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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