17 beta-hydroxysteroid dehydrogenase type XI localizes to human steroidogenic cells.
17 beta-hydroxysteroid dehydrogenase type XI localizes to human steroidogenic cells.
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发表时间：
2003
期刊：
影响因子：
4.8
通讯作者：
Z. Chai;P. Brereton;Takashi Suzuki;H. Sasano;V. Obeyesekere;G. Escher;R. Saffery;Peter Fuller
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作者：
Z. Chai;P. Brereton;Takashi Suzuki;H. Sasano;V. Obeyesekere;G. Escher;R. Saffery;Peter Fuller
我们搜索了表达序列标签数据库与短链醇脱氢酶超家族的保守结构域，并确定了另一种异构体的17 β-羟基类固醇脱氢酶，17 β HSDXI。这种酶将5 α-雄甾烷-3 α，17 β-二醇转化为雄甾酮。该底物与支持妊娠和调节γ-氨基丁酸受体活性有关。17 β HSDXI与人视网膜短链脱氢酶/还原酶retSDR 2共线性，retSDR 2是一种没有已知生物活性的蛋白质（登录号AAF 06939）。在已知功能的蛋白质中，17 β HSDXI与视黄醇代谢酶retSDR 1最密切相关，具有30%的同一性。在该cDNA序列的5'端非翻译区有一段15个腺苷的多态性片段，在C719 T处有一个沉默的多态性片段。发现具有一段20个腺苷的17 β HSDXI构建体比含有15个或更少腺苷的构建体产生显著更多的酶活性（43%对26%，P < 0.005）。C719 T多态性存在于15%的基因组DNA样本中。北方印迹分析显示17 β HSDXI在胰腺、肾、肝、肺、肾上腺、卵巢和心脏中的高水平表达。17 β-HSDXI的免疫组织化学染色在类固醇生成细胞如合体滋养细胞、皮脂腺、间质细胞和优势卵泡和黄体的颗粒细胞中很强。在肾上腺17 β HSDXI中，染色与17 α-羟化酶的分布共定位，但在中到外皮质中更强。17 β HSDXI也在胎儿中发现，并在出生后增加。肝实质细胞和子宫内膜及小肠上皮也被染色。在小鼠Y1细胞中的调节研究显示，cAMP下调17 β HSDXI酶活性（40%对32%，P < 0.05），并将基因表达降低至不可检测的水平。全反式维甲酸不影响17 β HSDXI的表达或活性，但与cAMP一起加入类维生素A显著降低了17 β HSDXI的活性（32%对23%，P < 0.05）。17 β HSDXI启动子的克隆和测序鉴定了潜在的核受体类固醇生成因子-1半位点TCCAAGGCCGG，并且在内含子1的远端部分发现了一簇其他三个潜在的类固醇生成因子-1半位点。总的来说，这些结果表明17 β HSDXI在类固醇生成过程中的雄激素代谢中的作用，以及在非类固醇生成组织中的可能作用，包括5 α-雄甾烷-3 α，17 β-二醇水平的旁分泌调节。17 β HSDXI可以通过代谢刺激类固醇合成的化合物和/或通过产生抑制类固醇合成的代谢物来起作用。
We searched expressed sequence tag databases with conserved domains of the short-chain alcohol dehydrogenase superfamily and identified another isoform of 17 beta-hydroxysteroid dehydrogenase, 17 beta HSDXI. This enzyme converts 5 alpha-androstane-3 alpha, 17 beta-diol to androsterone. The substrate has been implicated in supporting gestation and modulating gamma-aminobutyric acid receptor activity. 17 beta HSDXI is colinear with human retinal short-chain dehydrogenase/reductase retSDR2, a protein with no known biological activity (accession no. AAF06939). Of the proteins with known function, 17 beta HSDXI is most closely related to the retinol-metabolizing enzyme retSDR1, with which it has 30% identity. There is a polymorphic stretch of 15 adenosines in the 5' untranslated region of the cDNA sequence and a silent polymorphism at C719T. A 17 beta HSDXI construct with a stretch of 20 adenosines was found to produce significantly more enzyme activity than constructs containing 15 or less adenosines (43% vs. 26%, P < 0.005). The C719T polymorphism is present in 15% of genomic DNA samples. Northern blot analysis showed high levels of 17 beta HSDXI expression in the pancreas, kidney, liver, lung, adrenal, ovary, and heart. Immunohistochemical staining for 17 beta HSDXI is strong in steroidogenic cells such as syncytiotrophoblasts, sebaceous gland, Leydig cells, and granulosa cells of the dominant follicle and corpus luteum. In the adrenal 17 beta HSDXI, staining colocalized with the distribution of 17 alpha-hydroxylase but was stronger in the mid to outer cortex. 17 beta HSDXI was also found in the fetus and increased after birth. Liver parenchymal cells and epithelium of the endometrium and small intestine also stained. Regulation studies in mouse Y1 cells showed that cAMP down-regulates 17 beta HSDXI enzymatic activity (40% vs. 32%, P < 0.05) and reduces gene expression to undetectable levels. All-trans-retinoic acid did not affect 17 beta HSDXI expression or activity, but addition of the retinoid together with cAMP significantly decreased activity over cAMP alone (32% vs. 23%, P < 0.05). Cloning and sequencing of the 17 beta HSDXI promoter identified the potential nuclear receptor steroidogenic factor-1 half-site TCCAAGGCCGG, and a cluster of three other potential steroidogenic factor-1 half-sites were found in the distal part of intron 1. Collectively, these results suggest a role for 17 beta HSDXI in androgen metabolism during steroidogenesis and a possible role in nonsteroidogenic tissues including paracrine modulation of 5 alpha-androstane-3 alpha, 17 beta-diol levels. 17 beta HSDXI could act by metabolizing compounds that stimulate steroid synthesis and/or by generating metabolites that inhibit it.