Steroidogenic factor-1 mediates cyclic 3′,5′-adenosine monophosphate regulation of the high density lipoprotein receptor
Steroidogenic factor-1 mediates cyclic 3′,5′-adenosine monophosphate regulation of the high density lipoprotein receptor
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DOI：
10.1210/en.140.7.3034
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发表时间：
1999-07-01
期刊：
影响因子：
4.8
通讯作者：
McLean, MP
中科院分区：
文献类型：
--
作者：
Lopez, D;Sandhoff, TW;McLean, MP
高密度脂蛋白（HDL）受体介导肾上腺和性腺中HDL颗粒对胆固醇和胆固醇酯（类固醇生成的底物）的摄取。我们在这里报告，1 mM（Bu），cAMP处理大鼠黄体细胞24小时显着诱导（118倍）HDL受体信使RNA水平。大鼠HDL受体启动子含有类固醇生成因子-1（SF-1）结合位点（SFBd; 5 ′-TCAAGGCC-3 ′），SF-1蛋白通过该结合位点结合并激活该基因在人HTB 9膀胱癌和小鼠Y1肿瘤细胞中的转录，cAMP增强了该作用。这些观察结果表明，该基序是必需的基础和cAMP诱导的HDL受体基因的调节。在Kin 8细胞中的共转染研究表明，一个功能性PKA是cAMP诱导HDL受体基因转录所必需的，Kin 8细胞是一个Y1细胞系，其对cAMP活化具有抗性，这是由于蛋白激酶A（PKA）调节亚基的突变。删除激活功能-2域（氨基酸448-461）或突变Ser（430），SF-1蛋白中PKA的潜在共有磷酸化位点，降低HDL受体启动子的基础和cAMP诱导的激活。这些数据表明，SF-1蛋白中的这些区域是HDL受体基因的基础和cAMP诱导调节所必需的。通过SF-1介导HDL受体基因的cAMP反应性，表明这种反式作用因子在类固醇激素合成中是多么重要，因为它确保了所有必需的元素（底物和酶）在最大类固醇产生所需时都存在。
The high density lipoprotein (HDL) receptor mediates the uptake of cholesterol and cholesteryl esters, substrates for steroidogenesis, from an HDL particle in the adrenal gland and gonads. We report here that treatment of rat luteal cells with 1 mM (Bu),cAMP for 24 h dramatically induced (118-fold) HDL receptor messenger RNA levels. The rat HDL receptor promoter contains a steroidogenic factor-1 (SF-l)-binding site (SFBd; 5'-TCAAGGCC-3') through which SF-1 protein binds and activates transcription of this gene in both human HTB9 bladder carcinoma and mouse Y1 tumor cells, an effect that is enhanced by cAMP. These observations demonstrate that this motif is required for both basal and cAMP-induced regulation of the HDL receptor gene. Cotransfection studies in Kin 8 cells, a Y1 cell line resistant to cAMP activation as a result of a mutation in the protein kinase A (PKA) regulatory subunit, showed that a functional PKA is required for cAMP induction of HDL receptor gene transcription. Deleting the activation function-2 domain (amino acids 448-461) or mutating Ser(430), a potential consensus phosphorylation site for PKA in the SF-1 protein, decreased both basal and cAMP-induced activation of the HDL receptor promoter. These data suggest that these regions within the SF-1 protein are required for both basal and cAMP-induced regulation of the HDL receptor gene. The mediation of cAMP responsiveness of the HDL receptor gene by SF-1 suggests how important this trans-acting factor is in steroid hormone synthesis by assuring that all required elements (substrate and enzymes) are present when they are needed for maximal steroid production.