Adenosine 3′,5′‐monophosphate‐dependent protein kinase of leydig cells: In vitro activation and relationship to gonadotropin action upon cyclic AMP and steroidogenesis

Podestá, Ernesto J.; Dufau, Maria L.; Catt, Kevin J.

doi:10.1016/0014-5793(76)80760-0

Cited by 27 publications

(12 citation statements)

References 13 publications

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“…2 ). These results are in line with previous publications that indicate that steroidogenesis is dependent on the activity of PKA ( 49,50 ) and on phosphorylation and activation of StAR by PKA ( 51 ) and ERK ( 52 ). The sole increase in SHP2 and ACSL4 levels was not enough to increase steroid production because PKA and ERK activation are lacking.…”

Section: Role Of Acsl4 In Shp2-mediated Effect On Camp-stimulated Stesupporting

confidence: 93%

Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

Cooke¹,

Orlando²,

Maloberti

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org substrate preferences, enzyme kinetics, cellular and organelle locations, and regulation. ACSL4 has a marked preference for 20:4 (arachidonic acid, AA) and 20:5 (eicosapentaenoic acid). The high affi nity of ACSL4 for these fatty acids and the low affi nity for palmitic acid suggest that the enzyme plays a key role in the metabolism of AA. A second interesting feature of ACSL4 is its tissue distribution. In rats, its mRNA is expressed in various tissues, including the adrenal gland, epididymis, brain, lung, ovary, placenta, liver, and testis ( 6, 7 ). The striking feature of ACSL4 is its abundance in steroidogenic tissues, especially in zona fasciculata and reticularis of the rat adrenal gland, Leydig cells of the testis, and luteinized cells of the ovary ( 7 ). It is interesting that although relatively low or null expression levels of ACSL4 have been reported in other adult tissues ( 6, 7 ), this isoform is overexpressed in breast, prostate, colon, and liver cancer specimens ( 8-10 ).Regarding its function , ACSL4 is related to the acute regulation of steroid production in steroidogenic tissues. ACSL4 is a key protein ( 11 ) that works in concert with a mitochondrial acyl-CoA thioesterase, ACOT2 ( 12, 13 ). These two fatty acid-metabolizing enzymes constitute an AA generation/export system, which releases AA in the mitochondrion after the action of the steroidogenic hormones adrenocorticotropin hormone (ACTH) and luteinizing hormone (LH)/ chorionic gonadotropin (CG) ( 14 ). AA is then metabolized to lipoxygenated or epoxygenated products to induce the expression of the steroidogenesis acute regulatory (StAR) gene. StAR is a mitochondrial protein that, together with other proteins, participates in cholesterol transport to the inner mitochondrial membrane, which constitutes the rate-limiting Abstract Acyl-CoA synthetase 4 (ACSL4) is implicated in fatty acid metabolism with marked preference for arachidonic acid (AA). ACSL4 plays crucial roles in physiological functions such as steroid synthesis and in pathological processes such as tumorigenesis. However, factors regulating ACSL4 mRNA and/or protein levels are not fully described. Because ACSL4 protein expression requires tyrosine phosphatase activity, in this study we aimed to identify the tyrosine phosphatase involved in ACSL4 expression. NSC87877, a specifi c inhibitor of the tyrosine phosphatase SHP2, reduced ACSL4 protein levels in ACSL4-rich breast cancer cells and steroidogenic cells. Indeed, overexpression of an active form of SHP2 increased ACSL4 protein levels in MA-10 Leydig steroidogenic cells. SHP2 has to be activated through a cAMP-dependent pathway to exert its effect on ACSL4. The effects could be specifi cally attributed to SHP2 because knockdown of the phosphatase reduced ACSL4 mRNA and protein levels. Through the action on ACSL4 protein levels, SHP2 affected AA-CoA production and metabolism and, fi nally, the steroidogenic capacity of MA-10 cells: overexpression (or knockdown) of SHP2 led ...

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Section: Role Of Acsl4 In Shp2-mediated Effect On Camp-stimulated Stesupporting

confidence: 93%

Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

Cooke¹,

Orlando²,

Maloberti

et al. 2011

Journal of Lipid Research

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“…Stimulation of receptorbound cAMP levels and testosterone formation was observed within 15 min during incubation of Leydig cells with 1 pM hCG. At much higher hormone concentrations, as shown previously (6), cAMP levels were elevated within a few seconds, while testosterone production did not usually rise for about 10 min.…”

supporting

confidence: 54%

“…The major part of the hCG-induced rise in cAMP-independent protein kinase activity, corresponding to enzyme activation by endogenous cAMP, has been shown previously to be dissociated from the steroidogenic response (10). However, a minor increase in enzyme activity has been detectable over the hCG dose range that stimulated testosterone production.…”

mentioning

confidence: 89%

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

Dufau

Tsuruhara

Horner

et al. 1977

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

195

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“…1 upper, A). cAMP-dependent protein kinase was not shut off and its activation persisted for 30 min, as shown in Table 2 by the receptor-bound cAMP values and in previous reports in adrenal (2,30,31) and other steroid-elaborating tissue (32,33). The marked decrease in 32p incorporation in the case of the chase experiment (see Fig.…”

Section: Inhibition Of Protein Synthesis In Acth-stimulated Cellsmentioning

confidence: 56%

Adrenocorticotropin (ACTH) induces phosphorylation of a cytoplasmic protein in intact isolated adrenocortical cells.

Podestá¹,

Milani²,

Steffen³

et al. 1979

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

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In 32p incorporation experiments with intact adrenocortical cells, adrenocorticotropin (ACTH) or adenosine 3',5'-cyclic monophosphate (cAMP) induced a rapid and transient increase of approximately 300-500% in the phosphorylation of a 32P-containing cytoplasmic protein of about 150,000 daltons (APS15o). Half-maximal stimulation of APS150 phosphorylation was observed with about 3 pM ACTH. Receptorbound cAMP, corticosterone production, and the appearance of phosphorylated APS150 increased in parallel with respect to both time and ACTH concentration. All three responses were dependent on extracellular calcium. Inhibition of protein synthesis with cycloheximide suggested a half-life of APS150 of about 10 min. The time course of 32p incorporation into ACTH-induced APS150 in the absence and presence of nonradioactive phosphate shows that the phosphorylation of APS150 is under simultaneous control of cAMP-dependent protein kinase and of phosphatase activity. Thus a rapid ACTI-dependent and cAMP-dependent protein phosphorylation in intact adrenocortical cells within steroidogenic ACTH concentrations has now been demonstrated.It is well recognized that steroidogenesis in adrenal cortex and similar steroid-elaborating tissue is under complex hormonal control. In the current model of adrenocorticotropin (ACTH) action, it is proposed that the hormone binds to a specific receptor on plasma membrane and stimulates adenylate cyclase activity, with accumulation of adenosine 3',5'-cyclic monophosphate (cAMP) and activation of a cAMP-dependent protein kinase (1). Until recently, the intermediate role of cAMP in the acute steroidogenic response to physiological concentrations of ACTH has been questioned (1). However, it has now been shown that hormonal stimulation of adrenocortical cells by ACTH in the steroidogenic concentration range is accompanied by a simultaneous increase in endogenous cAMP bound to the regulatory subunit of the protein kinase (2). Furthermore, studies with mutant clones of Y1 adrenocortical tumor cells (adenylate cyclase and cAMP-dependent protein kinase deficiency) provide additional evidence that cAMP and cAMPdependent protein kinase are obligatory components of the ACTH-stimulated steroidogenesis pathway (3). In this context, the characterization of an endogenous specific substrate(s) for cAMP-dependent protein kinase(s) would substantially enlarge our understanding of the mechanism of acute ACTH action.Several laboratories have reported phosphorylation of subcellular proteins in broken cells of adrenocortical tissue (4-8). Ribosomal protein phosphorylation stimulated by ACTH and cAMP in cultured mouse tumor cells was also described (9). However, this stimulation was achieved only by high ACTH concentrations. It has been shown that the activity of enzymes involved in steroidogenesis is increased by phosphorylation. Evidence has been presented that in adrenal cortex the phos- [32Plphosphate (400 MCi/ml; 1 Ci = 3.7 X 10l°becquerels) for different times at 37°C or 0°C in a total volume of 0.7 ml; this...

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Adenosine 3′,5′‐monophosphate‐dependent protein kinase of leydig cells: In vitro activation and relationship to gonadotropin action upon cyclic AMP and steroidogenesis

Cited by 27 publications

References 13 publications

Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4

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

Adrenocorticotropin (ACTH) induces phosphorylation of a cytoplasmic protein in intact isolated adrenocortical cells.

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