This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dewi, D. A. Articles by Wheeler-Jones, C. P. D. Search for Related Content PubMed PubMed Citation Articles by Dewi, D. A. Articles by Wheeler-Jones, C. P. D.

Requirement for ERK1/2 Activation in the Regulation of Progesterone Production in Human Granulosa-Lutein Cells Is Stimulus Specific

Department of Veterinary Basic Sciences, Royal Veterinary College, London, United Kingdom NW1 0TU

Address all correspondence and requests for reprints to: Dr. Caroline P. D. Wheeler-Jones, Department of Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London, United Kingdom NW1 0TU. E-mail: . cwheeler{at}rvc.ac.uk

This study was conducted to determine whether the ERK1/2 family of MAPKs can be modulated by physiological regulators of the human corpus luteum, and whether this activation is important for progesterone secretion in human granulosa-lutein (hGL) cells. Human LH (hLH), hCG, and agents that indirectly elevate cAMP [cholera toxin, forskolin, (Bu)₂cAMP], time- and dose-dependently activated ERK1/2 in hGL cells. ERK1/2 activation was reduced by preincubation with PKA inhibitors, including myristoylated PKI, suggesting that cAMP mediates ERK1/2 activation. Two structurally distinct inhibitors of MAPK kinase (MEK), PD 98059 and U 0126, abrogated hLH/hCG-induced ERK1/2 activation, but had no effect on hLH-, hCG-, or 22R-hydroxycholesterol-stimulated progesterone secretion. In contrast, both inhibitors blocked cholera toxin-, forskolin-, and (Bu)₂cAMP-induced ERK1/2 phosphorylation concomitant with a reduction in progesterone secretion. The known luteotropin, PGE₂, promoted MEK- and cAMP-dependent activation of ERK1/2, and inhibitors of either MEK or PKA decreased PGE₂-induced progesterone synthesis. Our findings demonstrate that the requirement for ERK1/2 activation as a regulator of progesterone synthesis in hGL cells is stimulus dependent, and that the MEK inhibitor-sensitive step is distal to cAMP generation, but proximal to the conversion of cholesterol to pregnenolone.

This article has been cited by other articles:

				N. Andric and M. Ascoli The Luteinizing Hormone Receptor-Activated Extracellularly Regulated Kinase-1/2 Cascade Stimulates Epiregulin Release from Granulosa Cells Endocrinology, November 1, 2008; 149(11): 5549 - 5556. [Abstract] [Full Text] [PDF]

				C.-G. Liang, Y.-Q. Su, H.-Y. Fan, H. Schatten, and Q.-Y. Sun Mechanisms Regulating Oocyte Meiotic Resumption: Roles of Mitogen-Activated Protein Kinase Mol. Endocrinol., September 1, 2007; 21(9): 2037 - 2055. [Abstract] [Full Text] [PDF]

				S. Priyanka and R. Medhamurthy Characterization of cAMP/PKA/CREB signaling cascade in the bonnet monkey corpus luteum: expressions of inhibin-{alpha} and StAR during different functional status Mol. Hum. Reprod., June 1, 2007; 13(6): 381 - 390. [Abstract] [Full Text] [PDF]

				L M Thurston, D R E Abayasekara, and A E Michael 11{beta}-Hydroxysteroid dehydrogenase expression and activities in bovine granulosa cells and corpora lutea implicate corticosteroids in bovine ovarian physiology J. Endocrinol., May 1, 2007; 193(2): 299 - 310. [Abstract] [Full Text] [PDF]

				D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]

				P. R Manna, Y. Jo, and D. M Stocco Regulation of Leydig cell steroidogenesis by extracellular signal-regulated kinase 1/2: role of protein kinase A and protein kinase C signaling J. Endocrinol., April 1, 2007; 193(1): 53 - 63. [Abstract] [Full Text] [PDF]

				C. Stocco, C. Telleria, and G. Gibori The Molecular Control of Corpus Luteum Formation, Function, and Regression Endocr. Rev., February 1, 2007; 28(1): 117 - 149. [Abstract] [Full Text] [PDF]

				T. Miyoshi, F. Otsuka, K. Inagaki, H. Otani, M. Takeda, J. Suzuki, J. Goto, T. Ogura, and H. Makino Differential Regulation of Steroidogenesis by Bone Morphogenetic Proteins in Granulosa Cells: Involvement of Extracellularly Regulated Kinase Signaling and Oocyte Actions in Follicle-Stimulating Hormone-Induced Estrogen Production Endocrinology, January 1, 2007; 148(1): 337 - 345. [Abstract] [Full Text] [PDF]

				Y.-Q. Su, M. Nyegaard, M. T. Overgaard, J. Qiao, and L. C. Giudice Participation of Mitogen-Activated Protein Kinase in Luteinizing Hormone-Induced Differential Regulation of Steroidogenesis and Steroidogenic Gene Expression in Mural and Cumulus Granulosa Cells of Mouse Preovulatory Follicles Biol Reprod, December 1, 2006; 75(6): 859 - 867. [Abstract] [Full Text] [PDF]

				P. R Manna, S. P Chandrala, Y. Jo, and D. M Stocco cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation. J. Mol. Endocrinol., August 1, 2006; 37(1): 81 - 95. [Abstract] [Full Text] [PDF]

				V. K. Yadav and R. Medhamurthy Dynamic Changes in Mitogen-Activated Protein Kinase (MAPK) Activities in the Corpus Luteum of the Bonnet Monkey (Macaca radiata) during Development, Induced Luteolysis, and Simulated Early Pregnancy: A Role for p38 MAPK in the Regulation of Luteal Function Endocrinology, April 1, 2006; 147(4): 2018 - 2027. [Abstract] [Full Text] [PDF]

				P. R. Manna, S. P. Chandrala, S. R. King, Y. Jo, R. Counis, I. T. Huhtaniemi, and D. M. Stocco Molecular Mechanisms of Insulin-like Growth Factor-I Mediated Regulation of the Steroidogenic Acute Regulatory Protein in Mouse Leydig Cells Mol. Endocrinol., February 1, 2006; 20(2): 362 - 378. [Abstract] [Full Text] [PDF]

				J. A. MacLean II, M. K. Rao, K. M.H. Doyle, J. S. Richards, and M. F. Wilkinson Regulation of the Rhox5 Homeobox Gene in Primary Granulosa Cells: Preovulatory Expression and Dependence on SP1/SP3 and GABP Biol Reprod, December 1, 2005; 73(6): 1126 - 1134. [Abstract] [Full Text] [PDF]

				C.-G. Liang, L.-J. Huo, Z.-S. Zhong, D.-Y. Chen, H. Schatten, and Q.-Y. Sun Cyclic Adenosine 3',5'-Monophosphate-Dependent Activation of Mitogen-Activated Protein Kinase in Cumulus Cells Is Essential for Germinal Vesicle Breakdown of Porcine Cumulus-Enclosed Oocytes Endocrinology, October 1, 2005; 146(10): 4437 - 4444. [Abstract] [Full Text] [PDF]

				F.-Q. Yu, C.-S. Han, W. Yang, X. Jin, Z.-Y. Hu, and Y.-X. Liu Activation of the p38 MAPK pathway by follicle-stimulating hormone regulates steroidogenesis in granulosa cells differentially J. Endocrinol., July 1, 2005; 186(1): 85 - 96. [Abstract] [Full Text] [PDF]

				S. Sela-Abramovich, E. Chorev, D. Galiani, and N. Dekel Mitogen-Activated Protein Kinase Mediates Luteinizing Hormone-Induced Breakdown of Communication and Oocyte Maturation in Rat Ovarian Follicles Endocrinology, March 1, 2005; 146(3): 1236 - 1244. [Abstract] [Full Text] [PDF]

				M. Jo, M. C. Gieske, C. E. Payne, S. E. Wheeler-Price, J. B. Gieske, I. V. Ignatius, T. E. Curry Jr., and C. Ko Development and Application of a Rat Ovarian Gene Expression Database Endocrinology, November 1, 2004; 145(11): 5384 - 5396. [Abstract] [Full Text] [PDF]

				E C Chin, T E Harris, and D R E Abayasekara Changes in cAMP-dependent protein kinase (PKA) and progesterone secretion in luteinizing human granulosa cells J. Endocrinol., October 1, 2004; 183(1): 39 - 50. [Abstract] [Full Text] [PDF]

				E C Chin and D R E Abayasekara Progesterone secretion by luteinizing human granulosa cells: a possible cAMP-dependent but PKA-independent mechanism involved in its regulation J. Endocrinol., October 1, 2004; 183(1): 51 - 60. [Abstract] [Full Text] [PDF]

				T. Hirakawa and M. Ascoli 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 Mol. Endocrinol., November 1, 2003; 17(11): 2189 - 2200. [Abstract] [Full Text] [PDF]

				K. Tajima, A. Dantes, Z. Yao, K. Sorokina, F. Kotsuji, R. Seger, and A. Amsterdam Down-Regulation of Steroidogenic Response to Gonadotropins in Human and Rat Preovulatory Granulosa Cells Involves Mitogen-Activated Protein Kinase Activation and Modulation of DAX-1 and Steroidogenic Factor-1 J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2288 - 2299. [Abstract] [Full Text] [PDF]

				R. J. K. Anand, H.-J. Paust, K. Altenpohl, and A. K. Mukhopadhyay Regulation of Vascular Endothelial Growth Factor Production by Leydig Cells In Vitro: The Role of Protein Kinase A and Mitogen-Activated Protein Kinase Cascade Biol Reprod, May 1, 2003; 68(5): 1663 - 1673. [Abstract] [Full Text] [PDF]

				D. L. Russell, K. M. H. Doyle, I. Gonzales-Robayna, C. Pipaon, and J. S. Richards Egr-1 Induction in Rat Granulosa Cells by Follicle-Stimulating Hormone and Luteinizing Hormone: Combinatorial Regulation By Transcription Factors Cyclic Adenosine 3',5'-Monophosphate Regulatory Element Binding Protein, Serum Response Factor, Sp1, and Early Growth Response Factor-1 Mol. Endocrinol., April 1, 2003; 17(4): 520 - 533. [Abstract] [Full Text] [PDF]

				C. R. O. Carvalho, J. B. C. Carvalheira, M. H. M. Lima, S. F. Zimmerman, L. C. Caperuto, A. Amanso, A. L. Gasparetti, V. Meneghetti, L. F. Zimmerman, L. A. Velloso, et al. Novel Signal Transduction Pathway for Luteinizing Hormone and Its Interaction with Insulin: Activation of Janus Kinase/Signal Transducer and Activator of Transcription and Phosphoinositol 3-Kinase/Akt Pathways Endocrinology, February 1, 2003; 144(2): 638 - 647. [Abstract] [Full Text] [PDF]