Intermediate role of adenosine 3′:5′-cyclic monophosphate and protein kinase during gonadotropin-induced steroidogenesis in testicular interstitial cells

Dufau, Maria L.; Tsuruhara, T.; Horner, Kathleen; Podestá, Ernesto J.; Catt, Kevin J.

doi:10.1073/pnas.74.8.3419

Cited by 195 publications

(65 citation statements)

References 21 publications

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“…In order to test this hypothesis, studies of PTP activity were extended to another steroidogenic system, as Leydig cells, using fresh interstitial testicular and MA-10 cells, an established and well-characterized tumor Leydig cell line (Ascoli 1981, Stocco & Chaudhary 1990, Stocco & Ascoli 1993, Weiss-Messer et al 1998. Testosterone production by Leydig cells in the testis is triggered by luteinizing hormone (LH) through cell surface receptors coupled to a signaling transduction mechanism based on PKAmediated phosphorylation (Dufau et al 1977, Clark et al 1994, a similar pathway to ACTH-activated corticosteroid production in adrenal zona fasciculata (ZF) (Podestá et al 1979, Sala et al 1979.…”

Section: Introductionmentioning

confidence: 99%

LH/chorionic gonadotropin signaling pathway involves protein tyrosine phosphatase activity downstream of protein kinase A activation: evidence of an obligatory step in steroid production by Leydig cells

Maciel

Poderoso²,

Gorostizaga³

et al. 2001

Journal of Endocrinology

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Our recent reports indicate that protein tyrosine phosphorylation is an obligatory component of the mechanism of action of ACTH in its stimulatory action of corticosteroid production in adrenal zona fasciculata (ZF). The role of protein tyrosine phosphatase (PTP) activity in the regulation of steroidogenesis by LH/chorionic gonadotropin (CG) was tested using cell-permeable PTP inhibitors. Thus, PTP inhibition blocks LH-and 8-bromo-cAMP-stimulated testosterone production by Leydig cells without affecting 22(R)OH-cholesterolsupported steroidogenesis, similar results to those obtained in the adrenal ZF/ACTH system, leading us to propose that PTP action is an obligatory and common step in the cascade triggered by both hormones. Then, we continued the study testing whether LH modulates PTP activity in MA-10 cells, a Leydig cell line. In this regard, we observed by an in-gel PTP assay two PTPs of 110 and 50 kDa that are activated by hormone and 8-bromocAMP activation of the cells. Moreover, there is a transient increase by the second messenger in total PTP activity that correlates with the higher activity displayed by the 110 and 50 kDa proteins in the in-gel assay. In accordance with these results, analysis of tyrosine phosphorylated proteins showed the LH-induced dephosphorylation of proteins of 120, 68 and 50 kDa. The results of this study indicate that PTPs play an important role in the regulation of Leydig cell functions and that there exists a cross talk between serine/threonine phosphorylation and tyrosine dephosphorylation mediated by hormone-activated cAMP-dependent protein kinase and PTPs. These results are the first evidence of PTP having a role in LH/CGstimulated steroidogenesis.

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Section: Introductionmentioning

confidence: 99%

LH/chorionic gonadotropin signaling pathway involves protein tyrosine phosphatase activity downstream of protein kinase A activation: evidence of an obligatory step in steroid production by Leydig cells

Maciel

Poderoso²,

Gorostizaga³

et al. 2001

Journal of Endocrinology

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“…While LH is the major physiological agonist in most animals, its action can also be mimicked by chorionic gonadotropin (CG). The signal transduction cascade involved in LH/CG action includes increases in intracellular cAMP levels and activation of protein kinase A (PKA), events that also occur in adrenocorticotropin (ACTH)-stimulated steroid production in adrenal cortical cells (Cooke et al 1976, Dufau et al 1977, Podestá et al 1979, Rae et al 1979, Sala et al 1979, Wang & Ascoli 1990, Swinnen et al 1991. It is well recognized that one of the requirements for full steroidogenic activity in response to LH/CG and ACTH is the PKA-mediated phosphorylation of regulatory proteins (Pon et al 1986, Chaudary & Stocco 1991, Stocco & Clark 1993.…”

Section: Introductionmentioning

confidence: 99%

Protein tyrosine phosphatases are involved in LH/chorionic gonadotropin and 8Br-cAMP regulation of steroidogenesis and StAR protein levels in MA-10 Leydig cells

Paz

Maciel²,

Maloberti³

et al. 2002

Journal of Endocrinology

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The LH signal transduction pathway features the activation of protein tyrosine phosphatases (PTPs) as one of the components of a cascade that includes other well characterized events such as cAMP-dependent protein kinase A (PKA) activation. Moreover, the action of PTPs is required to increase the rate-limiting step in steroid biosynthesis, namely the cAMP-regulated transfer of cholesterol to the inner mitochondrial membrane. Since both PKA activity and steroidogenic acute regulatory (StAR) protein induction are obligatory steps in this transfer of cholesterol, the present study was performed to investigate the role of PTPs in the regulation of PKA activity and StAR expression in response to LH/chorionic gonadotropin (CG) and 8Br-cAMP in MA-10 cells. While the exposure of MA-10 cells to the PTP inhibitor, phenylarsine oxide (PAO), did not modify PKA activity, it partially inhibited the effect of human CG and cAMP analog on StAR protein levels. Time-course studies demonstrated that PAO inhibited cAMP induction of StAR protein and mRNA. At 30 min, the effect on cAMPstimulated StAR protein levels was a 35% inhibition, progressing to up to 90% inhibition at 120 min of stimulation. The maximal inhibitory effect on cAMP-induced StAR mRNA level was obtained at 60 min (85%). In summary, these results demonstrate that inhibition of PTP activity affected both StAR protein and mRNA synthesis and suggest that the activity of hormone-regulated PTPs is a requirement in the LH signaling cascade that results in the up-regulation of StAR protein and, subsequently, increased steroid synthesis.

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“…Also, the experiments with Leydig cell extracts revealed that several of the proteins showing cyclic AMPdependent phosphorylation were coincident with those observed in intact cells during hormone action. In the Leydig cell, increases in cyclic AMP and stimulation of cyclic AMP-dependent protein kinase have been observed within 1-2 min after hCG stimulation in vitro [1][2][3][4][5]. Therefore, it is not surprising that prominent increases in phosphorylation were detectable at 5 and 10 min.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were incubated with purified hCG (CR119, 10 000 IU]mg, or dibutyryl cyclic AMP (Bt2cAMP; Becton Dickenson and Co, Rutherford NJ). Testosterone and cyclic AMP production were measured in incubation media by direct radioimmunoassay as in [1,7].…”

Section: Preparation and Incubation Of Leydig Cellsmentioning

confidence: 99%

“…In the Leydig cell, the acute steroidogenic response to trophic hormone stimulation appears to be mediated by a highly compartmentalized activation pathway, in which minute increments in cAMP production cause a dose-related increase in protein kinase activity and testosterone biosynthesis [1][2][3][4][5]. These changes are preceded by corresponding increases in the binding of cyclic AMP to the regulatory subunit of the predominant type I protein kinase holoenzyme of the Leydig cell cytosol [1,6].…”

Section: Introductionmentioning

confidence: 99%

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Gonadotropin‐induced phosphorylation of endogenous proteins in the Leydig cell

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Intermediate role of adenosine 3′:5′-cyclic monophosphate and protein kinase during gonadotropin-induced steroidogenesis in testicular interstitial cells

Abstract: Discrepancies between adenosine 3':5'-cyclic monophosphate (cAMP)

Cited by 195 publications

References 21 publications

LH/chorionic gonadotropin signaling pathway involves protein tyrosine phosphatase activity downstream of protein kinase A activation: evidence of an obligatory step in steroid production by Leydig cells

LH/chorionic gonadotropin signaling pathway involves protein tyrosine phosphatase activity downstream of protein kinase A activation: evidence of an obligatory step in steroid production by Leydig cells

Protein tyrosine phosphatases are involved in LH/chorionic gonadotropin and 8Br-cAMP regulation of steroidogenesis and StAR protein levels in MA-10 Leydig cells

Gonadotropin‐induced phosphorylation of endogenous proteins in the Leydig cell

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