PMID- 25140527
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 8
DP  - 2014
TI  - Transforming growth factor-beta1 signaling represses testicular steroidogenesis 
      through cross-talk with orphan nuclear receptor Nur77.
PG  - e104812
LID - 10.1371/journal.pone.0104812 [doi]
LID - e104812
AB  - Transforming growth factor- beta1 (TGF-beta1) has been reported to inhibit luteinizing 
      hormone (LH) mediated-steroidogenesis in testicular Leydig cells. However, the 
      mechanism by which TGF-beta1 controls the steroidogenesis in Leydig cells is not 
      well understood. Here, we investigated the possibility that TGF-beta1 represses 
      steroidogenesis through cross-talk with the orphan nuclear receptor Nur77. Nur77, 
      which is induced by LH/cAMP signaling, is one of major transcription factors that 
      regulate the expression of steroidogenic genes in Leydig cells. TGF-beta1 signaling 
      inhibited cAMP-induced testosterone production and the expression of 
      steroidogenic genes such as P450c17, StAR and 3beta-HSD in mouse Leydig cells. 
      Further, TGF-beta1/ALK5 signaling repressed cAMP-induced and Nur77-activated 
      promoter activity of steroidogenic genes. In addition, TGF-beta1/ALK5-activated 
      Smad3 repressed Nur77 transactivation of steroidogenic gene promoters by 
      interfering with Nur77 binding to DNA. In primary Leydig cells isolated from 
      Tgfbr2flox/flox Cyp17iCre mice, TGF-beta1-mediated repression of cAMP-induced 
      steroidogenic gene expression was significantly less than that in primary Leydig 
      cells from Tgfbr2flox/flox mice. Taken together, these results suggest that 
      TGF-beta1/ALK5/Smad3 signaling represses the expression of steroidogenic genes via 
      the suppression of Nur77 transactivation in testicular Leydig cells. These 
      findings may provide a molecular mechanism involved in the TGF-beta1-mediated 
      repression of testicular steroidogenesis.
FAU - Park, Eunsook
AU  - Park E
AD  - Hormone Research Center, School of Biological Sciences and Technology, Chonnam 
      National University, Gwangju, Republic of Korea.
FAU - Song, Chin-Hee
AU  - Song CH
AD  - Hormone Research Center, School of Biological Sciences and Technology, Chonnam 
      National University, Gwangju, Republic of Korea.
FAU - Park, Jae-Il
AU  - Park JI
AD  - Korea Basic Science Institute, Gwangju Center at Chonnam National University, 
      Gwangju, Republic of Korea.
FAU - Ahn, Ryun-Sup
AU  - Ahn RS
AD  - Graduate School of Integrative Medicine, CHA Medical University, Seoul, Republic 
      of Korea.
FAU - Choi, Hueng-Sik
AU  - Choi HS
AD  - Hormone Research Center, School of Biological Sciences and Technology, Chonnam 
      National University, Gwangju, Republic of Korea.
FAU - Ko, CheMyong
AU  - Ko C
AD  - Department of Comparative Biosciences, College of Veterinary Medicine, University 
      of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
FAU - Lee, Keesook
AU  - Lee K
AD  - Hormone Research Center, School of Biological Sciences and Technology, Chonnam 
      National University, Gwangju, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140820
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Nuclear Receptor Subfamily 4, Group A, Member 1)
RN  - 0 (Phosphoproteins)
RN  - 0 (Smad3 Protein)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (steroidogenic acute regulatory protein)
RN  - 3XMK78S47O (Testosterone)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 1.1.- (3-Hydroxysteroid Dehydrogenases)
RN  - EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
SB  - IM
MH  - 3-Hydroxysteroid Dehydrogenases/genetics/metabolism
MH  - Animals
MH  - Cyclic AMP/pharmacology
MH  - Gene Expression Regulation, Enzymologic/drug effects/physiology
MH  - Leydig Cells/drug effects/metabolism/physiology
MH  - Male
MH  - Mice
MH  - Nuclear Receptor Subfamily 4, Group A, Member 1/*metabolism
MH  - Phosphoproteins/genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - Signal Transduction/drug effects/*physiology
MH  - Smad3 Protein/metabolism
MH  - Steroid 17-alpha-Hydroxylase/genetics/metabolism
MH  - Testis/drug effects/*metabolism
MH  - Testosterone/*biosynthesis
MH  - Transforming Growth Factor beta1/*metabolism
PMC - PMC4139307
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/08/21 06:00
MHDA- 2015/05/12 06:00
PMCR- 2014/08/20
CRDT- 2014/08/21 06:00
PHST- 2014/05/02 00:00 [received]
PHST- 2014/07/15 00:00 [accepted]
PHST- 2014/08/21 06:00 [entrez]
PHST- 2014/08/21 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
PHST- 2014/08/20 00:00 [pmc-release]
AID - PONE-D-14-19663 [pii]
AID - 10.1371/journal.pone.0104812 [doi]
PST - epublish
SO  - PLoS One. 2014 Aug 20;9(8):e104812. doi: 10.1371/journal.pone.0104812. 
      eCollection 2014.