p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene
p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene
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DOI：
10.1128/mcb.24.7.3057-3067.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Collins, S
中科院分区：
文献类型：
--
作者：
Cao, WH;Daniel, KW;Collins, S
已经证实，儿茶酚胺刺激的棕色脂肪产热需要环磷酸腺苷(CAMP)中的P-肾上腺素能升高，以增加解偶联蛋白1(UCP1)基因的表达。然而，对信号级联的下游成分或其相关的转录因子靶标知之甚少。在这里，我们证明了依赖cAMP和蛋白激酶A的p38丝裂原活化蛋白激酶(MAPK)在棕色脂肪细胞中的激活是小鼠UCP1基因转录过程中不可或缺的步骤。P38 MAPK通过磷酸化激活转录因子2(ATF-2)和过氧化物酶体增殖物激活受体γ(PPARGamma)辅助物1α(PGC-1α)两个不同的核因子家族成员，通过它们分别与UCP1基因关键增强子基序中的cAMP反应元件和PPAR反应元件相互作用来控制UCP1基因的表达。另外，p38MAPK激活ATF-2还可以作为cAMP感受器，增加棕色脂肪组织中PGC-1α基因的表达。综上所述，我们的发现表明，通过协调多种转录因子的活性，p38MAPK是促进产热的棕色脂肪cAMP信号机制的中心介体。
It is well established that catecholamine-stimulated thermogenesis in brown fat requires P-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-ctivated receptor gamma (PPARgamma) coativator 1alpha(PGC-1alpha) 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-1alpha 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.