p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene

Wenhong Cao, Kiefer W. Daniel, Jacques Robidoux, Pere Puigserver, Alexander V. Medvedev, Xu Bai, Lisa M. Floering, Bruce M. Spiegelman, Sheila Collins

Research output: Contribution to journalArticlepeer-review

Abstract

It is well established that catecholamine-stimulated thermogenesis in brown fat requires β-adrenergic elevations in cyclic AMP (cAMP) to increase expression of the uncoupling protein 1 (UCP1) gene. However, little is known about the downstream components of the signaling cascade or the relevant transcription factor targets thereof. Here we demonstrate that cAMP- and protein kinase A-dependent activation of p38 mitogen-activated protein kinase (MAPK) in brown adipocytes is an indispensable step in the transcription of the UCP1 gene in mice. By phosphorylating activating transcription factor 2 (ATF-2) and peroxisome proliferator-activated receptor gamma (PPAR-γ) coativator 1α (PGC-1α), members of two distinct nuclear factor families, p38 MAPK controls the expression of the UCP1 gene through their respective interactions with a cAMP response element and a PPAR response element that both reside within a critical enhancer motif of the UCP1 gene. Activation of ATF-2 by p38 MAPK additionally serves as the cAMP sensor that increases expression of the PGC-1α gene itself in brown adipose tissue. In conclusion, our findings illustrate that by orchestrating the activity of multiple transcription factors, p38 MAPK is a central mediator of the cAMP signaling mechanism of brown fat that promotes thermogenesis.

Original languageEnglish (US)
Pages (from-to)3057-3067
Number of pages11
JournalMolecular and Cellular Biology
Volume24
Issue number7
DOIs
StatePublished - Apr 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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