首页> 外文OA文献 >Retinol Dehydrogenase 10 but Not Retinol/Sterol Dehydrogenase(s) Regulates the Expression of Retinoic Acid-responsive Genes in Human Transgenic Skin Raft Culture*
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Retinol Dehydrogenase 10 but Not Retinol/Sterol Dehydrogenase(s) Regulates the Expression of Retinoic Acid-responsive Genes in Human Transgenic Skin Raft Culture*

机译:视黄醇脱氢酶10而非视黄醇/固醇脱氢酶调节人类转基因皮筏培养物中视黄酸响应基因的表达*

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摘要

Retinoic acid is essential for skin growth and differentiation, and its concentration in skin is controlled tightly. In humans, four different members of the short-chain dehydrogenase/reductase (SDR) superfamily of proteins were proposed to catalyze the rate-limiting step in the biosynthesis of retinoic acid (the oxidation of retinol to retinaldehyde). Epidermis contains at least three of these enzymes, but their relative importance for retinoic acid biosynthesis and regulation of gene expression during growth and differentiation of epidermis is not known. Here, we investigated the effect of the four human SDRs on retinoic acid biosynthesis, and their impact on growth and differentiation of keratinocytes using organotypic skin raft culture model of human epidermis. The results of this study demonstrate that ectopic expression of retinol dehydrogenase 10 (RDH10, SDR16C4) in skin rafts dramatically increases proliferation and inhibits differentiation of keratinocytes, consistent with the increased steady-state levels of retinoic acid and activation of retinoic acid-inducible genes in RDH10 rafts. In contrast, SDRs with dual retinol/sterol substrate specificity, namely retinol dehydrogenase 4 (RoDH4, SDR9C8), RoDH-like 3α-hydroxysteroid dehydrogenase (RL-HSD, SDR9C6), and RDH-like SDR (RDHL, SDR9C4) do not affect the expression of retinoic acid-inducible genes but alter the expression levels of several components of extracellular matrix. These results reveal essential differences in the metabolic contribution of RDH10 versus retinol/sterol dehydrogenases to retinoic acid biosynthesis and provide the first evidence that non-retinoid metabolic products of retinol/sterol dehydrogenases affect gene expression in human epidermis.
机译:维甲酸对皮肤的生长和分化至关重要,其在皮肤中的浓度受到严格控制。在人类中,提出了蛋白质的短链脱氢酶/还原酶(SDR)超家族的四个不同成员,以催化视黄酸生物合成(视黄醇氧化为视黄醛)中的限速步骤。表皮至少包含这些酶中的三种,但是在表皮生长和分化过程中它们对于视黄酸生物合成和基因表达调控的相对重要性尚不清楚。在这里,我们使用人类表皮的器官型筏培养模型研究了四种人类SDR对视黄酸生物合成的影响,以及它们对角质形成细胞生长和分化的影响。这项研究的结果表明,视黄醛脱氢酶10(RDH10,SDR16C4)在皮筏中的异位表达显着增加了增殖并抑制了角质形成细胞的分化,这与视黄酸稳态水平的增加和视黄酸诱导基因的激活相一致。 RDH10筏。相反,具有视黄醇/固醇双重底物特异性的SDR,即视黄醇脱氢酶4(RoDH4,SDR9C8),RoDH样3α-羟基类固醇脱氢酶(RL-HSD,SDR9C6)和RDH样SDR(RDHL,SDR9C4)不受影响维甲酸诱导基因的表达,但会改变细胞外基质中几种成分的表达水平。这些结果揭示了RDH10与视黄醇/固醇脱氢酶对视黄酸生物合成的代谢贡献的本质差异,并提供了视黄醇/固醇脱氢酶的非类视黄醇代谢产物影响人表皮基因表达的第一个证据。

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