The Lutropin/Choriogonadotropin Receptor-Induced Phosphorylation of the Extracellular Signal-Regulated Kinases in Leydig Cells Is Mediated by a Protein Kinase A-Dependent Activation of Ras

Hirakawa, Takashi; Ascoli, Mario

doi:10.1210/me.2003-0205

Cited by 83 publications

(83 citation statements)

References 57 publications

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“…Consistent with this, ERK1/2 inhibition has been demonstrated to decrease forskolin-stimulated pregnenolone synthesis in MA-10 cells, but in those studies the expression of the StAR protein was not determined (Gyles et al 2001). In human LH receptor expressing MA-10 cells, hCG was able to increase the PKA-mediated phosphorylation of Ras and ERK1/2 (Hirakawa & Ascoli 2003). Also, the effect of hCG on P-ERK1/2 was diminished by the inhibition of PKC and PKA responsiveness in immature rat Leydig cells (Martinelle et al 2004).…”

Section: Discussionmentioning

confidence: 82%

Regulation of Leydig cell steroidogenesis by extracellular signal-regulated kinase 1/2: role of protein kinase A and protein kinase C signaling

Manna

Stocco

2007

Journal of Endocrinology

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The steroidogenic acute regulatory (StAR) protein plays a central role in the regulation of steroid biosynthesis. While steroidogenesis is influenced by many processes, their modes of actions, in a few cases, remain obscure. In this study, we explored the mechanism of action of one such signaling pathway, the extracellular signal-regulated kinase 1/2 (ERK1/2), in regulating StAR expression and steroidogenesis in conjunction with the protein kinase A (PKA) and protein kinase C (PKC) pathways. Using MA-10 mouse Leydig tumor cells, we demonstrate that the activation of PKC and PKA signaling, by phorbol-12-myristate-13-acetate (PMA) and dibutyryl cAMP (dbcAMP)/human chorionic gonadotropin (hCG) respectively, was able to phosphorylate ERK1/2, an event markedly decreased by an upstream kinase inhibitor, U0126. Treatment with PMA enhanced StAR protein expression (associated with a slight increase in progesterone synthesis) but not its phosphorylation (PStAR), which, in contrast, coordinately increased in response to dbcAMP/hCG. Inhibition of ERK1/2 activity by U0126 decreased PMA-treated StAR expression but increased dbcAMP/hCG-mediated StAR and P-StAR; however, progesterone levels were attenuated. U0126 was found to affect StAR expression and steroidogenesis both at the transcriptional and translational levels. Further studies demonstrated that the effect of U0126 on PMA-and dbcAMP/hCG-mediated StAR expression and steroid synthesis was tightly correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) and scavenger receptor class B type 1 (SR-B1). In fact, both DAX-1 and SR-B1 appear to play important roles in hormone-regulated steroidogenesis. These findings clearly demonstrate that the ERK1/2 signaling cascade involved in regulating StAR expression and steroid synthesis is mediated by multiple factors and pathways and is stimulus specific in mouse Leydig cells.

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Section: Discussionmentioning

confidence: 82%

Regulation of Leydig cell steroidogenesis by extracellular signal-regulated kinase 1/2: role of protein kinase A and protein kinase C signaling

Manna

Stocco

2007

Journal of Endocrinology

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“…In addition, several reports have established the role of a possible cross-talk between cAMP/PKA and other signaling pathways such as MEK1/ERK or phosphatidylinositol 3-kinase/protein kinase B (Richards, 2001). In mouse Leydig cells, LH and 8Br-cAMP were shown to stimulate phosphorylation of ERK by PKA-dependent activation of Ras (Hirakawa and Ascoli, 2003). In human adrenal NCI-H295R cells, cAMP-mediated transcription of the CYP17 gene was demonstrated to be dependent on the activity of dual specificity phosphatase, which was later identified as MAPK phosphatase-1 (Sewer and Waterman, 2002).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2

Kempná

Hofer²,

Mullis³

et al. 2006

Mol Pharmacol

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Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3␤HSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor ␥ (PPAR␥) is the nuclear receptor for TZDs, suppression of PPAR␥ by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPAR␥. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.The gonads and the adrenals are the main sources of human androgens and express common genes for the biosynthesis of androgens. P450c17 and 3␤HSDII, encoded by the CYP17 and HSD3B2 genes, are key enzymes involved in biosynthesis of androgens. The mature adrenal cortex in humans produces androgens from cholesterol in a multistep pathway. In a first step, cholesterol is converted to pregnenolone by the P450 side-chain cleavage system. Second, pregnenolone then may be converted to 17␣-hydroxypregnenolone and to dehydroepiandrostenedione (DHEA) by the 17␣-hydroxylase and 17,20-lyase activities of P450c17. Third, DHEA is converted to androstenedione by 3␤-hydroxysteroid dehydrogenase type 2 (3␤HSDII). Although the fetal adrenals predominantly produce androgens, postnatal androgen production ceases only to resume at the age of 6 to 7 years, after the development of the zona reticularis, the third layer of the mature adrenal cortex.Thiazolidinediones (TZDs) are a class of oral insulin-sensitizing agents that are generally believed to exert their action as...

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“…Cyclic AMP, acting through PKA, activates Ras and the ERK1/2 cascade by mechanisms that remain to be investigated (dashed line #1). This pathway has been previously documented by the finding that overexpression of a cAMP phosphodiesterase (PDE), a PKA inhibitor (PKI) or a dominant-negative Ras (DN-Ras) inhibit the hCG-induced ERK1/2 response [6,7,9]. In addition, PKA-selective analogs of cAMP activate Ras and stimulate ERK1/2 phosphorylation whereas cAMP analogs that are selective for cAMPdependent guanine nucleotide exchange factors do not [8].…”

Section: -Discussionmentioning

confidence: 99%

“…The intracellular pathway is independent of Fyn, but is mediated by cAMP/PKA and it requires Ras activation [7]. The mechanisms by which cAMP/PKA activates Ras are unclear are unclear, however, as indicated by dashed arrow #1 in Figure 6.…”

Section: -Discussionmentioning

confidence: 99%

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Arrestin-3 is essential for the activation of Fyn by the luteinizing hormone receptor (LHR) in MA-10 cells☆

Galet

Ascoli

2008

Cellular Signalling

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Recent studies showed that Fyn is a mediator of the LHR-induced activation of the ERK1/2 cascade in MA-10 cells. Since the LHR is a G protein-coupled receptor and the Src family of kinases can be activated by some Gα subunits and by the non-visual arrestins we investigated the role of these signaling molecules in the LHR-provoked activation of Fyn.Small interfering RNAs (siRNAs) that target two Gα subunits that participate in LHR signaling (Gα s and Gα 11 ) and one that targets arrestin-3 were co-transfected with the hLHR in MA-10 cells. We then determined the effects of these siRNAs on the LHR-provoked activation of Fyn, the phosphorylation of FAK (a prominent Fyn substrate) and the release of EGF-like growth factors (a Fyn-mediated process).Expression of the siRNA against Gα s decreased the level of Gα s and LHR-stimulated cAMP production by ~50% but did not affect LHR-stimulated Fyn activation or FAK phosphorylation. Likewise, expression of the siRNA against Gα 11 decreased the level of Gα 11 and LHR-stimulated inositol phosphate production by ~50% but did not affect LHR-stimulated Fyn activation or FAK phosphorylation. Expression of the siRNA against arrestin-3 decreased the level of arrestin-3 and the rate of internalization of hCG by ~50% and it also inhibited the LHR-provoked stimulation of Fyn, the phosphorylation of FAK and the release of EGF-like growth factors.These results show that, in MA-10 cells, the hLHR activates Fyn through and arrestin-3-dependent pathway and that this pathway is a mediator of the hLHR-provoked release of EGF-like growth factors.

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The Lutropin/Choriogonadotropin Receptor-Induced Phosphorylation of the Extracellular Signal-Regulated Kinases in Leydig Cells Is Mediated by a Protein Kinase A-Dependent Activation of Ras

Cited by 83 publications

References 57 publications

Regulation of Leydig cell steroidogenesis by extracellular signal-regulated kinase 1/2: role of protein kinase A and protein kinase C signaling

Regulation of Leydig cell steroidogenesis by extracellular signal-regulated kinase 1/2: role of protein kinase A and protein kinase C signaling

Pioglitazone Inhibits Androgen Production in NCI-H295R Cells by Regulating Gene Expression of CYP17 and HSD3B2

Arrestin-3 is essential for the activation of Fyn by the luteinizing hormone receptor (LHR) in MA-10 cells☆

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