Interplay of PI3K and cAMP/PKA signaling, and rapamycin-hypersensitivity in TGFβ1 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells

Chen, Yun Jun; Hsiao, Pei-Wen; Lee, Ming Ting; Mason, J. Ian; Ke, Ferng Chun; Hwang, Juey Jen

doi:10.1677/joe-06-0076

Cited by 87 publications

(91 citation statements)

References 72 publications

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“…The effect of cAMP on the PI3Kinase pathway has been described to differ between cell types as the two main effectors of cAMP: protein kinase A and EPAC have been reported to have opposing effects on the pathway (Smith et al 2005, Chen et al 2007, Kwak et al 2008, Baviera et al 2010. In the present set of experiments, the effect of cAMP seems to be inhibitory on the FOXO3A/AKT1 phosphorylation.…”

Section: Phosphodiesterases In the Rat Ovarymentioning

confidence: 48%

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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Phosphodiesterases (PDEs) are important regulators of the intracellular cAMP concentration, which is a central second messenger that affects a multitude of intracellular functions. In the ovaries, cAMP exerts diverse functions, including regulation of ovulation and it has been suggested that augmented cAMP levels stimulate primordial follicle growth. The present study examined the gene expression, enzyme activity and immunolocalization of the different cAMP hydrolysing PDEs families in the rat ovary. Further, the effect of PDE4 inhibition on primordial follicle activation in cultured neonatal rat ovaries was also evaluated. We found varied expression of all eight families in the ovary with Pde7b and Pde8a having the highest expression each accounting for more than 20% of the total PDE mRNA. PDE4 accounted for 15-26% of the total PDE activity. Immunoreactive PDE11A was found in the oocytes and PDE2A in the corpora lutea. Incubating neonatal rat ovaries with PDE4 inhibitors did not increase primordial follicle activation or change the expression of the developing follicle markers Gdf9, Amh, Inha, the proliferation marker Mki67 or the primordial follicle marker Tmeff2. In addition, the cAMP analogue 8-bromo-cAMP did not increase AKT1 or FOXO3A phosphorylation associated with follicle activation or increase the expression of Kitlg known to be associated with follicle differentiation but did increase the Tmeff2, Mki67 and Inha expression in a dose-dependent manner. In conclusion, this study shows that both Pde7b and Pde8a are highly expressed in the rodent ovary and that PDE4 inhibition does not cause an increase in primordial follicle activation. Reproduction (2015) 150 11-20

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Section: Phosphodiesterases In the Rat Ovarymentioning

confidence: 48%

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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“…It is unlikely that this occurs through the inhibition of PKA activation and the subsequent reduction of PI3K activity and mTOR phosphorylation (22), considering that FSIP1 does not bind AKAP4 in our hands. Notwithstanding the absence of a putative mechanism, what is clear from our studies is the potential for targeting FSIP1 with small molecules, particularly for cancers that overexpress FSIP1 and HER2.…”

Section: Discussionmentioning

confidence: 72%

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

Liu

Zhang

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesisrelated testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-induced FSIP1 knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial-mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1 into nu/nu mice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1 gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial-mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1 on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy.GO analysis | KEGG pathway analysis | gene expression signature | breast cancer therapeutics

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“…Deficits in cAMP/PKA or cAMP/ERK signaling are viewed as one of the mechanisms for the behaviorial symptoms in depression (Breuillaud et al, 2012;Musazzi et al, 2010). There is interplay between the PI3K/Akt/FoxO and cAMP/PKA signaling pathways (Chen et al, 2007). FoxO1 is a direct substrate for PKA and PKA phosphorylates FoxO1 at Thr24, Ser256, and Ser319, three known Akt phosphorylation sites (Lee et al, 2011).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%