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Close kinship of human 20α‐hydroxysteroid dehydrogenase gene with three aldo‐keto reductase genes
Author(s) -
Nishizawa Mikio,
Nakajima Tatsuya,
Yasuda Katsuhiko,
Kanzaki Hideharu,
Sasaguri Yasuyuki,
Watanabe Kikuko,
Ito Seiji
Publication year - 2000
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1046/j.1365-2443.2000.00310.x
Subject(s) - biology , gene , hydroxysteroid dehydrogenase , microbiology and biotechnology , promoter , complementary dna , hydroxysteroid , hydroxysteroid dehydrogenases , gene expression , dehydrogenase , enzyme , biochemistry
Background 20α‐Hydroxysteroid dehydrogenase (HSD) is a member of the aldo‐keto reductase (AKR) superfamily and catalyses the reaction of progesterone to the inactive form 20α‐hydroxyprogesterone. Progesterone plays an important role in the maintenance of pregnancy, and, in rodents, plasma progesterone levels decrease abruptly just before parturition. The induction of 20α‐HSD is thought to be responsible for the decrease in plasma progesterone at term. High homology between human 20α‐HSD [AKR 1C1] cDNA with other AKRs had caused difficulty in gene isolation and expression analysis. Thus, the metabolism of progesterone in the human reproductive system remained unclear. Results By hybridization with rat 20α‐HSD [AKR 1C8] cDNA and high‐stringency polymerase chain reaction (PCR) with gene‐specific primers, we were able to isolate the human 20α‐HSD, bile acid‐binding protein (BABP) [AKR 1C2], prostaglandin F synthase (PGFS) [AKR 1C3], and dihydrodiol dehydrogenase (DD) 4 [AKR 1C4] genes. These genes had similar exon‐intron organizations and shared a high homology. The four recombinant enzymes encoded by these genes showed distinct substrate specificity. By reverse transcription‐PCR analysis, human 20α‐HSD, BABP and PGFS mRNAs were expressed ubiquitously, while DD4 mRNA was restricted to the liver. Promoter activities of the 20α‐HSD, BABP and PGFS genes were high, both in ovarian granulosa cells and hepatocytes. Radiation hybridization analysis revealed that all these genes were located close together in chromosome 10. Conclusion The human gene encoding for the progesterone‐metabolizing enzyme 20α‐HSD in the female reproductive system was cloned, and its expression and gene localization were elucidated. BABP, PGFS and DD4 genes, which were highly homologous to the 20α‐HSD gene, were also cloned, and their structure and function were characterized.