Protein kinase D regulates the adiponectin gene expression through phosphorylation of AP-2: A common pathway to the ABCA1 gene regulation
Protein kinase D regulates the adiponectin gene expression through phosphorylation of AP-2: A common pathway to the ABCA1 gene regulation
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DOI：
10.1016/j.atherosclerosis.2011.01.043
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发表时间：
2011-05-01
期刊：
影响因子：
5.3
通讯作者：
Yokoyama, Shinji
中科院分区：
文献类型：
--
作者：
Iwamoto, Noriyuki;Yokoyama, Shinji
激活蛋白（AP） 2 β的表达与2型糖尿病密切相关，并负向调节脂联素基因的表达。我们之前已经证明AP-2 α通过蛋白激酶（PK） d的ser磷酸化负调控atp结合盒A1 （ABCA1）基因。AP-2 α的磷酸化位点位于基本结构域，是其DNA结合的关键位点，在物种和5种AP-2亚型中是保守的。因此，我们研究了PKD在调节脂联素基因表达中的作用。通过其siRNA敲低PKD导致脂联素mRNA和启动子活性增加，导致培养细胞中脂联素分泌增加，脂肪堆积减少。PKD激活剂降低脂联素基因的表达，而PKD siRNA和选择性抑制剂Go6983对其的抑制抵消了这种作用。ChIP分析表明，PKD活性的抑制降低了AP-2 β与脂联素启动子的DNA结合。最后，Go6983增加了小鼠脂联素的表达。因此PKD是AP-2 α和AP-2 β DNA结合活性的共同调节剂，通过磷酸化分别负调控ABCA1和脂联素基因的表达。2011爱思唯尔爱尔兰有限公司版权所有。
Expression of the activator protein (AP) 2 beta is closely associated with type-2 diabetes and negatively regulates expression of the adiponectin gene. We previously demonstrated that AP-2 alpha negatively regulates the ATP-binding cassette A1 (ABCA1) gene through its Ser-phosphorylation by protein kinase (PK) D. The phosphorylation site of AP-2 alpha located in the basic domain, a critical site for its DNA binding, is conserved among species and five subtypes of AP-2. We therefore investigated the involvement of PKD in regulation of the adiponectin gene expression. Knockdown of PKD by its siRNA led to the increase in the mRNA and the promoter activity of adiponectin, and resulted in increase of adiponectin secretion and decrease of fat accumulation in cultured cells. PKD activators decreased expression of the adiponectin gene, and its inhibition by PKD siRNA and by a selective inhibitor Go6983 canceled this effect. ChIP analysis demonstrated that inhibition of PKD activity decreased the DNA binding of AP-2 beta to the adiponectin promoter. Finally, Go6983 increased adiponectin expression in mice. PKD is thus a common modulator of the DNA binding activity of AP-2 alpha and AP-2 beta through their phosphorylation for negative regulation of the ABCA1 and adiponectin genes expression, respectively. (C) 2011 Elsevier Ireland Ltd. All rights reserved.