title: Human glutathione S-transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF-1) and are involved in steroidogenesis.
abstract: Steroidogenic factor 1 (SF-1) is a master regulator for steroidogenesis. In this study, we identified novel SF-1 target genes using a genome-wide promoter tiling array and a DNA microarray. SF-1 was found to regulate human glutathione S-transferase A (GSTA) family genes (hGSTA1-hGSTA4), a superfamily of detoxification enzymes clustered on chromosome 6p12. All hGSTA genes were up-regulated by transduction of SF-1 into human mesenchymal stem cells, while knockdown of endogenous SF-1 in H295R cells down-regulated all hGSTA genes. Chromatin immunoprecipitation assays, however, revealed that SF-1 bound directly to the promoters of hGSTA3 and weakly of hGSTA4. Chromosome conformation capture assays revealed that the coordinated expression of the genes was based on changes in higher-order chromatin structure triggered by SF-1, which enables the formation of long-range interactions, at least between hGSTA1 and hGSTA3 gene promoters. In steroidogenesis, dehydrogenation of the 3-hydroxy group and subsequent Δ(5)-Δ(4) isomerization are thought to be enzymatic properties of 3β-hydroxysteroid dehydrogenase (3β-HSD). Here, we demonstrated that, in steroidogenic cells, the hGSTA1 and hGSTA3 gene products catalyze Δ(5)-Δ(4) isomerization in a coordinated fashion with 3β-HSD II to produce progesterone or Δ(4)-androstenedione from their Δ(5)-precursors. Thus, hGSTA1 and hGSTA3 gene products are new members of steroidogenesis working as Δ(5)-Δ(4) isomerases.
authors: Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan.
authors: Takehiro
authors: T
authors: Matsumura
authors: Yoshitaka
authors: Y
authors: Imamichi
authors: Tetsuya
authors: T
authors: Mizutani
authors: Yunfeng
authors: Y
authors: Ju
authors: Takashi
authors: T
authors: Yazawa
authors: Shinya
authors: S
authors: Kawabe
authors: Masafumi
authors: M
authors: Kanno
authors: Tadayuki
authors: T
authors: Ayabe
authors: Noriyuki
authors: N
authors: Katsumata
authors: Maki
authors: M
authors: Fukami
authors: Masaru
authors: M
authors: Inatani
authors: Yoshio
authors: Y
authors: Akagi
authors: Akihiro
authors: A
authors: Umezawa
authors: Tsutomu
authors: T
authors: Ogata
authors: Kaoru
authors: K
authors: Miyamoto
mesh_terms: D000735:Androstenedione / Q000096:biosynthesis; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000096:biosynthesis; D011375:Progesterone Reductase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D007527:Isoenzymes; D054339:Steroidogenic Factor 1; D013256:Steroids; D000735:Androstenedione; D011374:Progesterone; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; C495975:glutathione S-transferase A3-3, human; C119995:glutathione S-transferase alpha; C041116:leukotriene-C4 synthase
keywords: chromatin structure; gene cluster; isomerase activity; transcriptional regulation