Functional significance of the signal transduction pathways Akt and Erk in ovarian follicles:

School of Agriculture Food Science and Veterinary Medicine, Conway Institute, College of Life Science, University College Dublin, Belfield, Dublin 4, Ireland.
Journal of Ovarian Research (Impact Factor: 2.43). 02/2008; 1(1):2. DOI: 10.1186/1757-2215-1-2
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The intracellular signalling mechanisms that regulate ovarian follicle development are unclear; however, we have recently shown differences in the Akt and Erk signalling pathways in dominant compared to subordinate follicles. The aim of this study was to investigate the effects of inhibiting Akt and Erk phosphorylation on IGF- and gonadotropin- stimulated granulosa and theca cell function in vitro, and on follicle development in vivo.
Bovine granulosa and theca cells were cultured for six days and stimulated with FSH and/or IGF, or LH in combination with PD98059 (Erk inhibitor) and/or LY294002 (Akt inhibitor) and their effect on cell number and hormone secretion (estradiol, activin-A, inhibin-A, follistatin, progesterone and androstenedione) determined. In addition, ovarian follicles were treated in vivo with PD98059 and/or LY294002 in ewes on Day 3 of the cycle and follicles were recovered 48 hours later.
We have shown that gonadotropin- and IGF-stimulated hormone production by granulosa and theca cells is reduced by treatment with PD98059 and LY294002 in vitro. Furthermore, treatment with PD98059 and LY294002 reduced follicle growth and oestradiol production in vivo.
These results demonstrate an important functional role for the Akt and Erk signalling pathways in follicle function, growth and development.

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    • "This hormone has been shown to modulate phosphorylation of MAPK (ERK1/2, p38, and JNK; Di Simone et al. 2009, Chen et al. 2010), AKT (Palanivel et al. 2006), and AMPK (Satoh et al. 2004) in different cell types. These signaling pathways have been described to play a role in steroidogenesis and/or proliferation of GCs in response to various hormones such as FSH, IGF1, and insulin, as well as more recently to some adipokines including leptin and adiponectin (Moore et al. 2001, Kayampilly & Menon 2004, Tosca et al. 2005, Yu et al. 2005, Ryan et al. 2008, Kayampilly & Menon 2009). Since the majority of resistin effects on rat and bovine steroidogenesis and proliferation were observed from the physiological level (10 ng/ml) in our study, we then examined the effect of this dose on phosphorylation of AKT, ERK1/2, p38-MAPK, and AMPKa in bovine and rat GCs for 1–120 min. "
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    ABSTRACT: Resistin, initially identified in adipose tissue and macrophages, was implicated in insulin resistance. Recently, its mRNA was found in hypothalamo-pituitary axis and rat testis, leading us to hypothesize that resistin may be expressed in ovary. In this study, we determined in rats and cows 1) the characterization of resistin in ovary by RT-PCR, immunoblotting, and immunohistochemistry and 2) the effects of recombinant resistin (10, 100, 333, and 667 ng/ml) ± IGF1 (76 ng/ml) on steroidogenesis, proliferation, and signaling pathways of granulosa cells (GC) measured by enzyme immunoassay, [(3)H]thymidine incorporation, and immunoblotting respectively. We observed that resistin mRNA and protein were present in several bovine and rat ovarian cells. Nevertheless, only bovine GC abundantly expressed resistin mRNA and protein. Resistin treatment decreased basal but not IGF1-induced progesterone (P<0.05; whatever the dose) and estradiol (P<0.005; for 10 and 333 ng/ml) production by bovine GC. In rats, resistin (10 ng/ml) increased basal and IGF1-induced progesterone secretion (P<0.0001), without effect on estradiol release. We found no effect of resistin on rat GC proliferation. Conversely, in cows, resistin increased basal proliferation (P<0.0001; for 100-667 ng/ml) and decreased IGF1-induced proliferation of GC (P<0.0001; for 10-333 ng/ml) associated with a decrease in cyclin D2 protein level (P<0.0001). Finally, resistin stimulated AKT and p38-MAPK phosphorylation in both species, ERK1/2-MAPK phosphorylation in rats and had the opposite effect on the AMPK pathway (P<0.05). In conclusion, our results show that resistin is expressed in rat and bovine ovaries. Furthermore, it can modulate GC functions in basal state or in response to IGF1 in vitro.
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    • "In porcine endometrial cells, the LH hormone activates both cAMP/PKA and PLC/inositide tris-phosphate pathways [21]. Moreover, LH acting through the Akt and Erk pathways on theca cells plays a relevant function in vitro and follicle growth and development [22] "
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    • "Adiponectin rapidly and transiently activated ERK1/2 MAPK in bovine granulosa cells, as previously described in porcine, rat, chicken and human granulosa cells [2,15,16,40]. The ERK1/2 MAPK and/or Akt signaling pathways have been potentially involved in the steroid production in rat [50,51] and bovine [52,53] granulosa cells. To understand through which pathway adiponectin decreased insulin-induced steroidogenesis in bovine granulosa cells, we analyzed the pattern of ERK1/2 MAPK and Akt phosphorylation in bovine granulosa cells cultured with rh adiponectin (10 μg/mL) for 24 h and then with insulin (10-8 M) for 5 min. "
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