[PMID]: | 28457967 |
[Au] Autor: | Araya S; Kratschmar DV; Tsachaki M; Stücheli S; Beck KR; Odermatt A |
[Ad] Endereço: | Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. |
[Ti] Título: | DHRS7 (SDR34C1) - A new player in the regulation of androgen receptor function by inactivation of 5α-dihydrotestosterone? |
[So] Source: | J Steroid Biochem Mol Biol;171:288-295, 2017 07. |
[Is] ISSN: | 1879-1220 |
[Cp] País de publicação: | England |
[La] Idioma: | eng |
[Ab] Resumo: | DHRS7 (SDR34C1) has been associated with potential tumor suppressor effects in prostate cancer; however, its function remains largely unknown. Recent experiments using purified recombinant human DHRS7 suggested several potential substrates, including the steroids cortisone and Δ4-androstene-3,17-dione (androstenedione). However, the substrate and cofactor concentrations used in these experiments were very high and the physiological relevance of these observations needed to be further investigated. In the present study, recombinant human DHRS7 was expressed in intact HEK-293 cells in order to investigate whether glucocorticoids and androgens serve as substrates at sub-micromolar concentrations and at physiological cofactor concentrations. Furthermore, the membrane topology of DHRS7 was revisited using redox-sensitive green-fluorescent protein fusions in living cells. The results revealed that (1) cortisone is a substrate of DHRS7; however, it is not reduced to cortisol but to 20ß-dihydrocortisone, (2) androstenedione is not a relevant substrate of DHRS7, (3) DHRS7 catalyzes the oxoreduction of 5α-dihydrotestosterone (5αDHT) to 3α-androstanediol (3αAdiol), with a suppressive effect on androgen receptor (AR) transcriptional activity, and (4) DHRS7 is anchored in the endoplasmic reticulum membrane with a cytoplasmic orientation. Together, the results show that DHRS7 is a cytoplasmic oriented enzyme exhibiting 3α/20ß-hydroxysteroid dehydrogenase activity, with a possible role in the modulation of AR function. Further research needs to address the physiological relevance of DHRS7 in the inactivation of 5αDHT and AR regulation. |
[Mh] Termos MeSH primário: |
Androgênios/metabolismo Di-Hidrotestosterona/metabolismo Regulação para Baixo Retículo Endoplasmático/enzimologia Oxirredutases/metabolismo Receptores Androgênicos/metabolismo
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[Mh] Termos MeSH secundário: |
Androgênios/química Androstano-3,17-diol/química Androstano-3,17-diol/metabolismo Cortisona/análogos & derivados Cortisona/química Cortisona/metabolismo Di-Hidrotestosterona/química Glucocorticoides/metabolismo Proteínas de Fluorescência Verde/genética Proteínas de Fluorescência Verde/metabolismo Células HEK293 Seres Humanos Ligantes Conformação Molecular Oligopeptídeos/genética Oligopeptídeos/metabolismo Concentração Osmolar Oxirredução Oxirredutases/química Oxirredutases/genética Fragmentos de Peptídeos/química Fragmentos de Peptídeos/genética Fragmentos de Peptídeos/metabolismo Transporte Proteico Receptores Androgênicos/química Receptores Androgênicos/genética Proteínas Recombinantes de Fusão/metabolismo Proteínas Recombinantes/metabolismo Especificidade por Substrato
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (AR protein, human); 0 (Androgens); 0 (Glucocorticoids); 0 (Ligands); 0 (Oligopeptides); 0 (Peptide Fragments); 0 (Receptors, Androgen); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 08J2K08A3Y (Dihydrotestosterone); 147336-22-9 (Green Fluorescent Proteins); 25126-76-5 (Androstane-3,17-diol); 3615-87-0 (4-pregnene-17 alpha,20 beta,21-triol-3,11-dione); 98849-88-8 (FLAG peptide); EC 1.- (DHRS7 protein, human); EC 1.- (Oxidoreductases); V27W9254FZ (Cortisone) |
[Em] Mês de entrada: | 1707 |
[Cu] Atualização por classe: | 171208 |
[Lr] Data última revisão:
| 171208 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170502 |
[St] Status: | MEDLINE |
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