Novel Signal Transduction Pathway for Luteinizing Hormone and Its Interaction with Insulin: Activation of Janus Kinase/Signal Transducer and Activator of Transcription and Phosphoinositol 3-Kinase/Akt Pathways

Carvalho, Carla Roberta de Oliveira; Carvalheira, José Barreto Campello; Lima, Maria Helena Melo; Zimmerman, Suzana Ferreira; Caperuto, Luciana C.; Amanso, Angélica M.; Gasparetti, Alessandra L.; Meneghetti, Vainer; Zimmerman, Leonardo F.; Velloso, Lı́cio A.; Saad, Mário José Abdalla

doi:10.1210/en.2002-220706

Cited by 116 publications

(81 citation statements)

References 44 publications

(53 reference statements)

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“…FSH stimulated PI3K/AKT signal transduction in many cells, including granular cells, Sertoli cells, and oocytes [39][40][41]. FSH has also been shown to activate ERK and p38 mitogen-activated protein kinase (MAPK) in granulose cells [42,43].…”

Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

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Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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“…Furthermore, other hormones that act through GPCRs, including angiotensin II (AII), vasopressin, and luteinizing hormone (LH) can induce tyrosine phosphorylation of cytoplasm proteins (Marrero et al 1995;Saad et al 1995;Velloso et al 1996;Gallo-Payet and Guillon 1998;Carvalho et al 2003). AII and LH activate the cytosolic protein tyrosine kinase Janus kinase 2 (JAK2) and probably use this kinase to induce intracellular protein tyrosine phosphorylation.…”

mentioning

confidence: 99%

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

Anhê

Caperuto

Pereira-da-Silva

et al. 2004

Journal of Neurochemistry

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106

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Melatonin is the pineal hormone that acts via a pertussis toxinsensitive G-protein to inhibit adenylate cyclase. However, the intracellular signalling effects of melatonin are not completely understood. Melatonin receptors are mainly present in the suprachiasmatic nucleus (SCN) and pars tuberalis of both humans and rats. The SCN directly controls, amongst other mechanisms, the circadian rhythm of plasma glucose concentration. In this study, using immunoprecipitation and immunoblotting, we show that melatonin induces rapid tyrosine phosphorylation and activation of the insulin receptor b-subunit tyrosine kinase (IR) in the rat hypothalamic suprachiasmatic region. Upon IR activation, tyrosine phosphorylation of IRS-1 was detected. In addition, melatonin induced IRS-1/PI(3)-kinase and IRS-1/SHP-2 associations and downstream AKT serine phosphorylation and MAPK (mitogen-activated protein kinase) phosphorylation, respectively. These results not only indicate a new signal transduction pathway for melatonin, but also a potential cross-talk between melatonin and insulin.

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“…Activation of the JAK/STAT system in some non-ovarian cells in response to leptin, LH and insulin (Carvalho et al 2003) provides indirect evidence that STAT may mediate the effect on some hormones from the ovary. Direct evidence, especially in relation to ovarian cells, was absent.…”

Section: Is Stat1 Involved In Mediating the Effects Of Ghrelin On Pormentioning

confidence: 99%

“…Furthermore, activation of STAT1 phosphorylation after addition of leptin to human keratinocytes (Groschl et al 2005), and after LH and insulin treatment of rat ovary (Carvalho et al 2003), indicates that STAT1 can potentially mediate the effects of some hormones on ovarian cells. Nevertheless, there is no direct evidence for an involvement of STAT in mediating hormone action.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the transcription factor STAT1 in the regulation of porcine ovarian granulosa cell functions treated and not treated with ghrelin

Benco

Sirotkin²,

Vašíček³

et al. 2009

Reproduction

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The aim of our in vitro experiments was to study the role of the transcription factor STAT1 and the hormone ghrelin in controlling porcine ovarian function. The effects of treatment with ghrelin (0, 1, 10, 100 ng/ml), transfection-induced overexpression of transcription factor STAT1, and their combination on apoptosis (expression of apoptosis-related peptides caspase-3, BAX and anti-apoptotic peptide BCL2), proliferation (expression of proliferating cell nuclear antigene PCNA, proliferation-associated protein kinase MAPK/ERK1,2) and release of the hormones progesterone (P 4 ), prostaglandin F (PGF) and oxytocin (OXT) in cultured porcine ovarian granulosa cells was evaluated using RIA, immunocytochemistry and SDS-PAGE-western immunoblotting. It was found that ghrelin, when given alone, increased the expression of proliferation-associated PCNA and MAPK/ERK1,2, decreased the accumulation of apoptosis-related substances caspase-3, BAX, BCL2, decreased P 4 , and increased PGF and OXT release. Ghrelin tended to promote accumulation of STAT1 in both control and transfected cells, although in transfected cells ghrelin at 1 ng/ml decreased STAT1 accumulation. Transfection of porcine granulosa cells by a gene construct encoding STAT1 promoted the expression of STAT1 and apoptosis-related-BAX but the expression of BCL2 did not, and decreased the accumulation of proliferation-associated MAPK/ERK1,2 but not that of PCNA. It also promoted PGF and OXT but not P 4 release. Overexpression of STAT1 reversed the effect of ghrelin on STAT1, PCNA, PGF, OXT (from stimulatory to inhibitory), BCL2, P 4 (from inhibitory to stimulatory), prevented ghrelin effect on caspase-3 and BAX, but did not affect ghrelin's effect on MAPK/ERK1,2 expression. These results suggest that ghrelin directly affects porcine ovarian cells function -stimulates proliferation, inhibits apoptosis and affects secretory activity. Furthermore, they demonstrated the involvement of the transcription factor STAT1 in controlling these functions, the promotion of some markers of apoptosis (BAX), inhibition of some markers of proliferation (MAPK/ERK1,2) and stimulation of PGF release. Finally, the obtained data failed to demonstrate that STAT1 is involved in mediating the action of ghrelin on ovarian cell functions.

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Novel Signal Transduction Pathway for Luteinizing Hormone and Its Interaction with Insulin: Activation of Janus Kinase/Signal Transducer and Activator of Transcription and Phosphoinositol 3-Kinase/Akt Pathways

Cited by 116 publications

References 44 publications

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

Involvement of the transcription factor STAT1 in the regulation of porcine ovarian granulosa cell functions treated and not treated with ghrelin

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