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Transcriptional coactivator with PDZ-binding motif suppresses the expression of steroidogenic enzymes by nuclear receptor 4 A1 in Leydig cells

Title
Transcriptional coactivator with PDZ-binding motif suppresses the expression of steroidogenic enzymes by nuclear receptor 4 A1 in Leydig cells
Authors
Shin, Ji HyunLee, GibbeumJeong, Mi GyeongKim, Hyo KyeongWon, Hee YeonChoi, YujeongLee, Ji-HyeokNam, MisoChoi, Cheol SooHwang, Geum-SookHwang, Eun Sook
Ewha Authors
황은숙
SCOPUS Author ID
황은숙scopus
Journal Title
FASEB JOURNAL
ISSN
0892-6638JCR Link

1530-6860JCR Link
Citation
FASEB JOURNAL
Keywords
Leydig cellmitochondrial dysfunctionsteroidogenesisTAZtestosterone
Publisher
WILEY
Indexed
SCIE; SCOPUS WOS
Document Type
Article

Early Access
Abstract
Transcriptional coactivator with PDZ-binding motif (TAZ) plays crucial role in maintaining testicular structure and function via regulation of senescence of spermatogenic cells. However, it remains unclear whether TAZ is involved in testosterone biosynthesis in testicular Leydig cells. We found that TAZ deficiency caused aberrant Leydig cell expansion and increased lipid droplet formation, which was significantly associated with increased lipogenic enzyme expression. Additionally, the expression of key steroidogenic enzymes, including steroidogenic acute regulatory protein, cytochrome P450 (CYP) 11A1, CYP17A1, and 3 beta-hydroxysteroid dehydrogenase, was greatly increased in TAZ-deficient testes and primary Leydig cells. Interestingly, the transcriptional activity of nuclear receptor 4 A1 (NR4A1) was dramatically suppressed by TAZ; however, the protein expression and the subcellular localization of NR4A1 were not affected by TAZ. TAZ directly associated with the N-terminal region of NR4A1 and substantially suppressed its DNA-binding and transcriptional activities. Stable expression of TAZ in the mouse Leydig TM3 cell line decreased the expression of key steroidogenic enzymes, whereas knockdown of endogenous TAZ in TM3 cells increased transcripts of steroidogenic genes induced by NR4A1. Consistently, testosterone production was enhanced within TAZ-deficient Leydig cells. However, TAZ deficiency resulted in decreased testosterone secretion caused by dysfunctional mitochondria and lysosomes. Therefore, TAZ plays essential role in NR4A1-induced steroidogenic enzyme expression and testosterone production in Leydig cells.
DOI
10.1096/fj.201900695RRRR
Appears in Collections:
약학대학 > 약학과 > Journal papers
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