Norepinephrine specifically stimulates ribonucleotide reductase subunit R2 gene expression in proliferating brown adipocytes: Mediation via a cAMP/PKA pathway involving Src and Erk1/2 kinases
Norepinephrine specifically stimulates ribonucleotide reductase subunit R2 gene expression in proliferating brown adipocytes: Mediation via a cAMP/PKA pathway involving Src and Erk1/2 kinases
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DOI：
10.1006/excr.2002.5470
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发表时间：
2002-04-01
影响因子：
3.7
通讯作者：
Nedergaard, J
中科院分区：
文献类型：
--
作者：
Fredriksson, JM;Nedergaard, J
我们研究了在棕色脂肪细胞的发育过程中，核糖核苷酸还原酶(RNR)基因对生理cAMP提高剂去甲肾上腺素(NE)的影响是否发生了质的变化。在增殖细胞中，RNR亚基基因R1和R2的基础表达水平较高，但随着脂肪细胞的分化而显著下调。NE刺激促进棕色前脂肪细胞的DNA合成和增殖，导致增殖细胞中R2基因的表达增加(1.6倍)，但对R1的表达没有影响。相反，NE对融合分化的棕色脂肪细胞的刺激减少了R1和R2的表达。去甲肾上腺素刺激前脂肪细胞R2的表达可被Forsklin模拟，并被H89阻断，表明这是通过cAMP和蛋白激酶A(PKA)介导的。此外，Src和ERK1/2激酶的抑制剂显著减少NE刺激的R2的表达。我们得出结论：在棕色脂肪细胞发育的增殖期，肾上腺素能刺激棕色脂肪细胞特异性地上调RNR亚单位R2基因的表达，其中介途径是cAMP/PKA级联反应，进一步涉及到Src和MAP激酶Erk1/2。这些结果表明，肾上腺素能刺激棕色脂肪细胞的增殖可能作用于RNR活性限制亚基R2的基因表达水平，并表明R2基因对cAMP提高剂的反应发生了质的变化，这是细胞状态从增殖转换到分化的结果。(C)2002年埃尔塞维尔科学公司(美国)。
We have examined whether a qualitative switch occurs in the response of the ribonucleotide reductase (RNR) genes to the effect of the physiological cAMP-elevating agent norepinephrine (NE) during the development of brown adipocytes. Basal expression of the genes for both RNR subunits, R1 and R2, was high in proliferating cells, but was markedly down-regulated in parallel with adipocyte differentiation. NE stimulation, which promotes DNA synthesis and proliferation of brown preadipocytes, resulted in an increased expression of the R2 gene in proliferating cells (1.6-fold), but was without effect on R1 expression. In contrast, NE stimulation of confluent differentiating brown adipocytes reduced both R1 and R2 expression. The NE stimulation of R2 expression in preadipocytes was mimicked by forskolin and abolished by H89, demonstrating mediation via cAMP and protein kinase A (PKA). Also, inhibitors of Src and of Erk1/2 kinases markedly reduced NE-stimulated R2 expression. We conclude that adrenergic stimulation of brown adipocytes by NE specifically elevates expression of the RNR subunit R2 gene in the proliferative stage of brown adipocyte development, the mediating pathway being a cAMP/PKA cascade further involving Src and the MAP kinase Erkl/2. These results suggest that adrenergic stimulation of brown adipocyte proliferation may act at the level of gene expression of the limiting subunit for RNR activity, R2, and demonstrate a qualitative switch in the response of the R2 gene to cAMP-elevating agents as a consequence of the switch from proliferating to differentiating cell status. (C) 2002 Elsevier Science (USA).