Extracellular Signal-Regulated Kinases Are Involved in the Acute Activation of Steroidogenesis in Immature Rat Leydig Cells by Human Chorionic Gonadotropin

Martinelle, Nina; Holst, Mikael; Söder, Olle; Svechnikov, Konstantin

doi:10.1210/en.2004-0496

Cited by 85 publications

(83 citation statements)

References 20 publications

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“…Consistent with this, inhibition of MEK was demonstrated to enhance basal-and LH-stimulated StAR expression, but attenuate steroid synthesis both in primary and in mouse Leydig tumor cells (Martinat et al 2005), an observation in agreement with IGF-I responsive steroidogenesis (Manna et al 2006). MEK inhibition has also been associated with hCG-responsive decrease (Gyles et al 2001, Martinelle et al 2004) and LH/FSH-mediated increase (Seger et al 2001, Tajima et al 2003 in StAR expression and steroid synthesis in gonadal cells. We have previously demonstrated that inhibition of MEK was capable of decreasing EGF-and (Bu) 2 cAMP-responsive StAR expression and steroid synthesis in mouse Leydig cells (Manna et al 2002a).…”

Section: Discussionsupporting

confidence: 69%

“…In addition, longer-term incubation with cAMP-independent factors in mLTC-1 cells was associated with positive (IGF-I and FGF) and negative (EGF, IL-1, and CSF-1) effects on [ Conflicting results for the role of the MAPK/ERK signaling cascade in regulating StAR expression and steroidogenesis in different steroidogenic cells have been demonstrated (Gyles et al 2001, Seger et al 2001, Tai et al 2001, Dewi et al 2002, Manna et al 2002a, 2006, Seto-Young et al 2003, Tajima et al 2003, Martinelle et al 2004. For example, inhibition of MAPK/ERK (MEK) activity with PD98059 and U0126 has been shown to be associated with stimulation (Seger et al 2001, Tajima et al 2003, inhibition (Gyles et al 2001, Manna et al 2002a, Martinelle et al 2004, or no effect (Tai et al 2001, Seto-Young et al 2003, Tajima et al 2005) on the steroidogenic response. In the present study, different factors were found to stimulate MAPK signaling to various levels as determined using a pathdetect Elk-1 trans-reporting assay.…”

Section: Discussionmentioning

confidence: 99%

“…Cooke (1999), and Stocco et al (2005)). These studies demonstrated that the protein kinase C (PKC) signaling plays an important role in regulating StAR expression and steroidogenesis (Pilon et al 2003, as has the mitogen-activated protein kinase (MAPK) family of Ser-Thr kinases (Gyles et al 2001, Seger et al 2001, Manna et al 2002a, Martinelle et al 2004, Martinat et al 2005. In addition, StAR's transcriptional regulation has been shown to be mediated by several transcription factors, including the cAMP-response element-binding protein (CREB) and dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) (Manna et al 2002b, 2006, Clem et al 2005.…”

Section: Introductionmentioning

confidence: 99%

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cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Manna¹,

Chandrala²,

Jo³

et al. 2006

Journal of Molecular Endocrinology

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In the regulation of steroid biosynthesis, a process mediated by the steroidogenic acute regulatory (StAR) protein, both cAMP-dependent and -independent pathways are involved. While the cAMP-dependent regulatory events represent, by far, the most robust increase in steroid synthesis and are well established, the knowledge regarding cAMP-independent mechanisms is lacking. The present investigation was designed to elucidate the potential involvement of the latter in regulating StAR expression and steroidogenesis in mouse Leydig tumor cells (mLTC-1 cells). Treatment of mLTC-1 cells with a number of factors including insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), fibroblast growth factor, transforming growth factor (TGF)a, interleukin-1 (IL-1), and colony-stimulating factor-1, increased the levels of StAR mRNA, StAR protein, and progesterone to varying degrees and utilized signaling pathways that are not associated with elevations in intracellular cAMP levels. Importantly, phosphorylation of StAR in response to these stimuli was undetectable, which is in marked contrast to observations with human chorionic gonadotropin (hCG), indicating factors that do not alter intracellular cAMP, regulate the steroid biosynthesis in a StAR phosphorylation-independent manner. In addition, the roles for factors involved in cross-talk between the protein kinase pathways, PKA and PKC, were demonstrated. Further characterization of signaling by one such cAMP-independent factor, TGFa, demonstrated that the mechanism, whereby it increased StAR expression and steroid synthesis, was dependent on de novo protein synthesis and mediated via activation of the EGF receptor. TGFa was also able to augment hCG-stimulated cAMP synthesis, StAR protein and StAR phosphorylation, and influence hCG binding and LH receptor mRNA expression. Furthermore, TGFa increased phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP-response element-binding protein (CREB), processes inhibited by the mitogen-activated protein kinase/ERK inhibitor U0126 and by expression of non-phosphorylatable CREB-M1 respectively. Inhibition of ERK activity enhanced TGFa-mediated StAR protein expression (but not its phosphorylation) and decreased progesterone synthesis, events 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). Collectively, these findings demonstrate that, in mouse Leydig cells, cAMPindependent signaling events regulate steroidogenesis in a StAR phosphorylation-independent manner.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Manna¹,

Chandrala²,

Jo³

et al. 2006

Journal of Molecular Endocrinology

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show abstract

“…We observed that LH treatment increased ERK1/2 phosphorylation in a dose-and timedependent manner. A role for MAPK/ERK signaling in regulating gonadotropin-induced steroidogenesis in mammalian and avian granulosa cells (Moore et al 2001, Seger et al 2001, Dewi et al 2002, Cottom et al 2003, Su et al 2006, Woods & Johnson 2007 and in rat Leydig cells (Martinelle et al 2004) has also been reported. Although LH-induced P 4 synthesis by the mouse/rat uteri has been documented earlier (Bonnamy et al 1989, Mukherjee et al 1994, Debnath et al 2000, little is known about its mechanism of action.…”

Section: Discussionmentioning

confidence: 96%

“…We further observed that LH-stimulated ERK1/2 phosphorylation leading to increased P 4 production is significantly inhibited by PD98059, suggesting that action of LH on ERK1/2 phosphorylation is mediated by upstream MEK1/2. Although involvement of MAPK in mediating gonadotropin-stimulated steroidogenesis has been observed in many species, conflicting results in different steroidogenic tissues have been demonstrated (Seger et al 2001, Dewi et al 2002, Manna et al 2002, Seto-Young et al 2003, Martinelle et al 2004, Tajima et al 2005. For example, inhibition of MAPK/ERK1/2 activity with PD98059 and U0126 has been shown to be associated with stimulation (Seger et al 2001, Tajima et al 2003, inhibition (Gyles et al 2001, Manna et al 2002, Martinelle et al 2004, or no effect (Tai et al 2001, Seto-Young et al 2003, Tajima et al 2005) on steroidogenic response.…”

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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Effects of luteinizing hormone receptor signaling in prostate cancer cells

et al. 2014

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Extracellular Signal-Regulated Kinases Are Involved in the Acute Activation of Steroidogenesis in Immature Rat Leydig Cells by Human Chorionic Gonadotropin

Cited by 85 publications

References 20 publications

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

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

Effects of luteinizing hormone receptor signaling in prostate cancer cells

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