p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene

W Cao, KW Daniel, J Robidoux… - … and cellular biology, 2004 - Taylor & Francis
W Cao, KW Daniel, J Robidoux, P Puigserver, AV Medvedev, X Bai, LM Floering…
Molecular and cellular biology, 2004Taylor & Francis
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 …
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 (PPARγ) 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.
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