A Mitochondrial Kinase Complex Is Essential to Mediate an ERK1/2-Dependent Phosphorylation of a Key Regulatory Protein in Steroid Biosynthesis

Poderoso, Cecilia; Converso, Daniela P.; Maloberti, Paula; Duarte, Alejandra; Neuman, Isabel; Galli, Soledad; Maciel, Fabiana Cornejo; Paz, Cristina; Carreras, Marı́a Cecilia; Poderoso, Juan José; Podestá, Ernesto J.

doi:10.1371/journal.pone.0001443

Cited by 110 publications

(142 citation statements)

References 66 publications

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“…Examination of the mechanism involved indicates that cAMP participates in, but does not reproduce, p44/p42 mapk activation by ACTH (Roy et al 2011), as ACTH is more efficient in increasing p44/p42 mapk phosphorylation than forskolin or cAMP analogs. Phosphorylated p44/p42 mapk was observed in the cytoplasm rather than in the nucleus, supporting the view that localization of p44/p42 mapk in the cytoplasm may be associated with cellular differentiation, such as steroid biosynthesis or hypertrophy or (Poderoso et al 2008).…”

Section: Involvement Of Mapk Pathwayssupporting

confidence: 72%

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet

2016

Journal of Molecular Endocrinology

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The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo–pituitary–adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH.

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Section: Involvement Of Mapk Pathwayssupporting

confidence: 72%

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet

2016

Journal of Molecular Endocrinology

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“…Activation of these kinases are involved in cell survival and apoptosis in granulosa cells (Westfall et al 2000, Peter & Dhanasekaran 2003, Rak-Mardyła & Gregoraszczuk 2010. Besides the important mitogenic activity of ERK1/2 in the nucleus, ERK1/2 is localised in the mitochondria and plays a role in cell survival/ apoptosis (Poderoso et al 2008). JAK/STAT signalling is essential for numerous developmental and homeostatic processes, including cell apoptosis (Rawlings et al 2004).…”

Section: Mechanism Of Resistin Anti-apoptotic Actionmentioning

confidence: 99%

Resistin is a survival factor for porcine ovarian follicular cells

Rak¹,

Drwal²,

Wróbel³

et al. 2015

Reproduction

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Previously, we demonstrated the expression of resistin in the porcine ovary, the regulation of its expression and its direct effect on ovarian steroidogenesis. The objective of this study was to examine the effect of resistin on cell proliferation and apoptosis in a co-culture model of porcine granulosa and theca cells. First, we analysed the effect of resistin at 1 and 10 ng/ml alone or in combination with FSHand IGF1 on ovarian cell proliferation with an alamarBlue assay and protein expression of cyclins A and B using western blot. Next, the mRNA and protein expression of selected pro-apoptotic and pro-survival regulators of cell apoptosis, caspase-9, -8 and -3 activity and DNA fragmentation using real time PCR, western blot, fluorescent assay and an ELISA kit, respectively, were analysed after resistin treatment. Furthermore, we determined the effect of resistin on the protein expression of ERK1/2, Stat and Akt kinase. Using specific inhibitors of these kinases, we also checked caspase-3 activity and protein expression. We found that resistin, at both doses, has no effect on cell proliferation. The results showed that resistin decreased pro-apoptotic genes, which was confirmed on protein expression of selected factors. We demonstrate an inhibitory effect of resistin on caspase activity and DNA fragmentation. Finally, resistin stimulated phosphorylation of the ERK1/2, Stat and Akt and kinases inhibitors reversed resistin action on caspase-3 activity and protein expression to control. All of these results showed that resistin has an inhibitory effect on porcine ovarian cell apoptosis by activation of the MAPK/ERK, JAK/Stat and Akt/PI3 kinase signalling pathways. Reproduction (2015) 150 343-355

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“…In our present study, we also observed a stimulatory role of Lh on Star gene expression in mouse endometrium for P 4 production. Available information also indicated that in gonads and adrenal tissue, there is a phosphorylation of STAR by the PKA-MEK1/2-ERK1/2 pathway that is necessary for normal steroid synthesis (Gyles et al 2001, Poderoso et al 2008.…”

Section: Discussionmentioning

confidence: 99%

Expression of LH receptor in nonpregnant mouse endometrium: LH induction of 3β-HSD and de novo synthesis of progesterone

Kundu

Pramanick

Paul

et al. 2012

Journal of Endocrinology

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In mouse uterus, at the late diestrus stage LH binding sites have previously been described. The aim of our study was to confirm the existence of LH receptor (Lhr (Lhcgr)) mRNA and its protein in mouse endometrium. Endometrium at all stages of the estrous cycle contained Lhr mRNA, essentially identical to that found in mouse ovary. Endometrium also contained a 72 kDa immunoreactive receptor protein that bound to mouse anti-LHR antibody in western blot. Both receptor mRNA and protein were maximally expressed in the endometrium at metestrus and LH caused a significant increase in their expression levels. Endometrium also contained 3b-hydroxy steroid dehydrogenase (3b-hsd) mRNA and 3b-HSD protein. LH addition elevated their expression and activity as evident from increased conversion of labeled pregnenolone to progesterone (P 4 ) and de novo P 4 synthesis. LH-induced endometrial P 4 synthesis is mediated through expression of steroidogenic acute regulatory (Star) gene. Results demonstrated that LH-induced P 4 synthesis in endometrium is possibly mediated through the cAMP pathway. Involvement of a MAPK pathway was also evident. Gonadotropin-stimulated endometrial P 4 synthesis was markedly attenuated by an antagonist of MEK1/2, PD98059. LH-stimulated MEK1/2-dependent phosphorylation of ERK1/2 in a concentration-and time-dependant manner in cultured endometrial tissues. Moreover, involvement of cAMP in LH-stimulated activation of ERK1/2 was also evident. It is therefore possible that the major signaling pathways regulating endometrial steroidogenesis in mouse, including the adenylate cyclase and MAP kinase pathways, converge at a point distal to activation of protein kinase A and ERK1/2.

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A Mitochondrial Kinase Complex Is Essential to Mediate an ERK1/2-Dependent Phosphorylation of a Key Regulatory Protein in Steroid Biosynthesis

Cited by 110 publications

References 66 publications

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Resistin is a survival factor for porcine ovarian follicular cells

Expression of LH receptor in nonpregnant mouse endometrium: LH induction of 3β-HSD and de novo synthesis of progesterone

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