Journal article
Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad
The Journal of biological chemistry, Vol.280(10), pp.9135-9148
03/11/2005
Handle:
https://hdl.handle.net/2376/115607
PMCID: PMC1564190
PMID: 15613482
Abstract
Ovarian follicles undergo exponential growth in response to follicle-stimulating hormone (FSH), largely as a result of the proliferation of granulosa cells (GCs).
In vitro
under serum-free conditions, rat GCs differentiate in response to FSH but do not proliferate unless activin is also present. In the presence of FSH plus activin, GCs exhibit enhanced expression of cyclin D2 as well as inhibin-α, aromatase, steroidogenic factor-1 (SF-1), cholesterol side chain (SCC), and epiregulin. In this report we sought to identify the signaling pathways by which FSH and activin promote GC proliferation and differentiation. Our results show that these responses are associated with prolonged Akt phosphorylation relative to time-matched controls and are dependent on phosphati-dylinositol 3-kinase (PI 3-kinase) and Smad2/3 signaling, based on the ability of the PI 3-kinase inhibitor LY294002 or infection with adenoviral dominant negative Smad3 (DN-Smad3) mutant to attenuate induction of cyclin D2, inhibin-α, aromatase, SCC, SF-1, and epiregulin. The DN-Smad3 mutant also abolished prolonged Akt phosphorylation stimulated by FSH plus activin 24 h post-treatment. Infection with the adenoviral constitutively active forkhead box-containing protein, O subfamily (FOXO)1 mutant suppressed induction of cyclin D2, aromatase, inhibin-α, SF-1, and epiregulin. Transient transfections of GCs with constitutively active FOXO1 mutant also suppressed cyclin D2, inhibin-α, and epiregulin promoter-reporter activities. Chromatin immunoprecipitation results demonstrate
in vivo
the association of FOXO1 with the cyclin D2 promoter in untreated GCs and release of FOXO1 from the cyclin D2 promoter upon addition of FSH plus activin. These results suggest that proliferation and differentiation of GCs in response to FSH plus activin requires both removal of FOXO1-dependent repression and positive signaling from Smad2/3.
Metrics
12 Record Views
Details
- Title
- Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad
- Creators
- Youngkyu Park - From the Departments of Cell and Molecular Biology andEvelyn T Maizels - From the Departments of Cell and Molecular Biology andZachary J Feiger - From the Departments of Cell and Molecular Biology andHena Alam - From the Departments of Cell and Molecular Biology andCarl A Peters - From the Departments of Cell and Molecular Biology andTeresa K Woodruff - Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, and theTerry G Unterman - Department of Medicine, University of Illinois College of Medicine and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612Eun Jig Lee - Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, and theJ. Larry Jameson - Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, and theMary Hunzicker-Dunn - From the Departments of Cell and Molecular Biology and
- Publication Details
- The Journal of biological chemistry, Vol.280(10), pp.9135-9148
- Academic Unit
- Molecular Biosciences, School of
- Identifiers
- 99900547997701842
- Language
- English
- Resource Type
- Journal article