PMID- 17283241
OWN - NLM
STAT- MEDLINE
DCOM- 20070412
LR  - 20211203
IS  - 0022-0795 (Print)
IS  - 0022-0795 (Linking)
VI  - 192
IP  - 2
DP  - 2007 Feb
TI  - Interplay of PI3K and cAMP/PKA signaling, and rapamycin-hypersensitivity in 
      TGFbeta1 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa 
      cells.
PG  - 405-19
AB  - Transforming growth factor (TGF) beta1 facilitates FSH-induced differentiation of 
      rat ovarian granulosa cells. The signaling crosstalk between follicle stimulating 
      hormone (FSH) and TGFbeta receptors remains unclear. This study was to 
      investigate the interplay of cAMP/protein kinase A (PKA) and 
      phosphatidylinositol-3-kinase (PI3K) signaling including mammalian target of 
      rapamycin (mTOR)C1 dependence in FSH- and TGFbeta1-stimulated steroidogenesis in 
      rat granulosa cells. To achieve this aim, inhibitors of PKA (PKAI), PI3K 
      (wortmannin), and mTORC1 (rapamycin) were employed. PKAI and wortmannin 
      suppressions of the FSH-increased progesterone production were partly attributed 
      to decreased level of 3beta-HSD, and their suppression of the FSH plus TGFbeta1 
      effect was attributed to the reduction of all the three key players, 
      steroidogenic acute regulatory (StAR) protein, P450scc, and 3beta-HSD. Further, 
      FSH activated the PI3K pathway including increased integrin-linked kinase (ILK) 
      activity and phosphorylation of Akt(S473), mTOR(S2481), S6K(T389), and 
      transcription factors particularly FoxO1(S256) and FoxO3a(S253), which were 
      reduced by wortmannin treatment but not by PKAI. Interestingly, PKAI suppression 
      of FSH-induced phosphorylation of cAMP regulatory element-binding protein 
      (CREB(S133)) disappeared in the presence of wortmannin, suggesting that 
      wortmannin may affect intracellular compartmentalization of signaling 
      molecule(s). In addition, TGFbeta1 had no effect on FSH-activated CREB and PI3K 
      signaling mediators. We further found that rapamycin reduced the 
      TGFbeta1-enhancing effect of FSH-stimulated steroidogenesis, yet it exhibited no 
      effect on FSH action. Surprisingly, rapamycin displayed a suppressive effect at 
      concentrations that had no effect on mTORC1 activity. Together, this study 
      demonstrates a delicate interplay between cAMP/PKA and PI3K signaling in FSH and 
      TGFbeta1 regulation of steroidogenesis in rat granulosa cells. Furthermore, we 
      demonstrate for the first time that TGFbeta1 acts in a rapamycin-hypersensitive 
      and mTORC1-independent manner in augmenting FSH-stimulated steroidogenesis in rat 
      granulosa cells.
FAU - Chen, Yun-Ju
AU  - Chen YJ
AD  - Institute of Physiology, School of Medicine, National Yang-Ming University, 155 
      Linong Street, Section 2, Taipei 112, Taiwan, Republic of China.
FAU - Hsiao, Pei-Wen
AU  - Hsiao PW
FAU - Lee, Ming-Ting
AU  - Lee MT
FAU - Mason, J Ian
AU  - Mason JI
FAU - Ke, Ferng-Chun
AU  - Ke FC
FAU - Hwang, Jiuan-Jiuan
AU  - Hwang JJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Endocrinol
JT  - The Journal of endocrinology
JID - 0375363
RN  - 0 (Androstadienes)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (steroidogenic acute regulatory protein)
RN  - 4G7DS2Q64Y (Progesterone)
RN  - 9002-68-0 (Follicle Stimulating Hormone)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 1.1.- (3-Hydroxysteroid Dehydrogenases)
RN  - EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (integrin-linked kinase)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - 3-Hydroxysteroid Dehydrogenases/metabolism
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Cells, Cultured
MH  - Cholesterol Side-Chain Cleavage Enzyme/metabolism
MH  - Cyclic AMP/*metabolism
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Follicle Stimulating Hormone/pharmacology
MH  - Granulosa Cells/drug effects/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Progesterone/analysis/*biosynthesis
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/physiology
MH  - Sirolimus/metabolism/pharmacology
MH  - Stimulation, Chemical
MH  - TOR Serine-Threonine Kinases
MH  - Transforming Growth Factor beta1/metabolism/*pharmacology
MH  - Wortmannin
EDAT- 2007/02/07 09:00
MHDA- 2007/04/14 09:00
CRDT- 2007/02/07 09:00
PHST- 2007/02/07 09:00 [pubmed]
PHST- 2007/04/14 09:00 [medline]
PHST- 2007/02/07 09:00 [entrez]
AID - 192/2/405 [pii]
AID - 10.1677/JOE-06-0076 [doi]
PST - ppublish
SO  - J Endocrinol. 2007 Feb;192(2):405-19. doi: 10.1677/JOE-06-0076.