The Src Tyrosine Kinase Pathway Regulates Thecal CYP17 Expression and Androstenedione Secretion

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2008 Jul 22

PMID 18642057

Citations 4

Authors

Gaurav Chaturvedi

Koji Arai

Paul F Terranova

Katherine F Roby

Affiliations

Soon will be listed here.

Abstract

In order to evaluate the role of Src tyrosine kinase in thecal cell steroidogenesis, a pharmacological approach was utilized by treating enriched populations of mouse ovarian theca-interstitial cells in vitro with a direct Src kinase inhibitor, PP2. Inhibition of Src with PP2 increased both basal and forskolin-stimulated androstenedione secretion, and increased cytochrome P450 17-alpha hydroxylase-lyase (CYP17) promoter activity and steady state mRNA. PP2 did not change thecal levels of StAR mRNA. Inhibition of mitogen-activated protein kinase kinase, a downstream regulator of Src activity, using PD98059 also increased forskolin-stimulated secretion of androstenedione above forskolin alone, but had no effect on basal secretion of androstenedione. Src inhibition increased mitogen-activated protein kinase phosphatase-1 protein and decreased phosphorylation of SF-1, which correlated with increased CYP17 promoter activity and mRNA levels. These results implicate Src tyrosine kinase in the regulation of CYP17 and thecal androgen secretion.

Citing Articles

Insulin resistance enhances the mitogen-activated protein kinase signaling pathway in ovarian granulosa cells.

Kong L, Wang Q, Jin J, Xiang Z, Chen T, Shen S PLoS One. 2017; 12(11):e0188029.

PMID: 29125859 PMC: 5695281. DOI: 10.1371/journal.pone.0188029.

Paracrine Regulation of Steroidogenesis in Theca Cells by Granulosa Cells Derived from Mouse Preantral Follicles.

Liu X, Qiao P, Jiang A, Jiang J, Han H, Wang L Biomed Res Int. 2015; 2015:925691.

PMID: 26357661 PMC: 4556819. DOI: 10.1155/2015/925691.

Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell.

Wu S, Divall S, Nwaopara A, Radovick S, Wondisford F, Ko C Diabetes. 2014; 63(4):1270-82.

PMID: 24379345 PMC: 3964497. DOI: 10.2337/db13-1514.

Involvement of Src family of kinases and cAMP phosphodiesterase in the luteinizing hormone/chorionic gonadotropin receptor-mediated signaling in the corpus luteum of monkey.

Kunal S, Killivalavan A, Medhamurthy R Reprod Biol Endocrinol. 2012; 10:25.

PMID: 22455442 PMC: 3353251. DOI: 10.1186/1477-7827-10-25.

References

Taniguchi F, Harada T, Deura I, Iwabe T, Tsukihara S, Terakawa N . Hepatocyte growth factor promotes cell proliferation and inhibits progesterone secretion via PKA and MAPK pathways in a human granulosa cell line. Mol Reprod Dev. 2004; 68(3):335-44. DOI: 10.1002/mrd.20076. View

Sirianni R, Carr B, Pezzi V, Rainey W . A role for src tyrosine kinase in regulating adrenal aldosterone production. J Mol Endocrinol. 2001; 26(3):207-15. DOI: 10.1677/jme.0.0260207. View

Martinat N, Crepieux P, Reiter E, Guillou F . Extracellular signal-regulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression. Reprod Nutr Dev. 2005; 45(1):101-8. DOI: 10.1051/rnd:2005007. View

Taylor C . Src tyrosine kinase-induced loss of luteinizing hormone responsiveness is via a Ras-dependent, phosphatidylinositol-3-kinase independent pathway. Biol Reprod. 2002; 67(3):789-94. DOI: 10.1095/biolreprod.101.000976. View

Schulte T, Blagosklonny M, Ingui C, Neckers L . Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J Biol Chem. 1995; 270(41):24585-8. DOI: 10.1074/jbc.270.41.24585. View

Blake R, Broome M, Liu X, Wu J, Gishizky M, Sun L . SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Mol Cell Biol. 2000; 20(23):9018-27. PMC: 86555. DOI: 10.1128/MCB.20.23.9018-9027.2000. View

Chaturvedi G, Arai K, Limback D, Roby K, Terranova P . Src tyrosine kinase regulates CYP17 expression and androstenedione secretion in theca-enriched mouse ovarian cells. Endocrine. 2005; 25(2):147-54. DOI: 10.1385/ENDO:25:2:147. View

Beshay V, Havelock J, Sirianni R, Ye P, Suzuki T, Rainey W . The mechanism for protein kinase C inhibition of androgen production and 17alpha-hydroxylase expression in a theca cell tumor model. J Clin Endocrinol Metab. 2007; 92(12):4802-9. DOI: 10.1210/jc.2007-1394. View

Zhang P, Mellon S . The orphan nuclear receptor steroidogenic factor-1 regulates the cyclic adenosine 3',5'-monophosphate-mediated transcriptional activation of rat cytochrome P450c17 (17 alpha-hydroxylase/c17-20 lyase). Mol Endocrinol. 1996; 10(2):147-58. DOI: 10.1210/mend.10.2.8825555. View

10.

Sewer M, Waterman M . CAMP-dependent protein kinase enhances CYP17 transcription via MKP-1 activation in H295R human adrenocortical cells. J Biol Chem. 2002; 278(10):8106-11. DOI: 10.1074/jbc.M210264200. View

11.

Touyz R, He G, Wu X, Park J, Mabrouk M, Schiffrin E . Src is an important mediator of extracellular signal-regulated kinase 1/2-dependent growth signaling by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients. Hypertension. 2001; 38(1):56-64. DOI: 10.1161/01.hyp.38.1.56. View

12.

Sirianni R, Carr B, Ando S, Rainey W . Inhibition of Src tyrosine kinase stimulates adrenal androgen production. J Mol Endocrinol. 2003; 30(3):287-99. DOI: 10.1677/jme.0.0300287. View

13.

TAYLOR C . Platelet-derived growth factor activates porcine thecal cell phosphatidylinositol-3-kinase-Akt/PKB and ras-extracellular signal-regulated kinase-1/2 kinase signaling pathways via the platelet-derived growth factor-beta receptor. Endocrinology. 2000; 141(4):1545-53. DOI: 10.1210/endo.141.4.7415. View

14.

Tai C, Kang S, Choi K, Tzeng C, Leung P . Role of mitogen-activated protein kinase in prostaglandin f(2alpha) action in human granulosa-luteal cells. J Clin Endocrinol Metab. 2001; 86(1):375-80. DOI: 10.1210/jcem.86.1.7159. View

15.

Wu C, Chen Y, Wang J, Hsieh M, Yeh C, Shin S . Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway. Br J Cancer. 2002; 87(9):1000-5. PMC: 2364317. DOI: 10.1038/sj.bjc.6600589. View

16.

Kypta R, Goldberg Y, Ulug E, Courtneidge S . Association between the PDGF receptor and members of the src family of tyrosine kinases. Cell. 1990; 62(3):481-92. DOI: 10.1016/0092-8674(90)90013-5. View

17.

Nelson-Degrave V, Wickenheisser J, Hendricks K, Asano T, Fujishiro M, Legro R . Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol. 2004; 19(2):379-90. DOI: 10.1210/me.2004-0178. View

18.

Bromann P, Korkaya H, Courtneidge S . The interplay between Src family kinases and receptor tyrosine kinases. Oncogene. 2004; 23(48):7957-68. DOI: 10.1038/sj.onc.1208079. View

19.

Bromann P, Korkaya H, Webb C, Miller J, Calvin T, Courtneidge S . Platelet-derived growth factor stimulates Src-dependent mRNA stabilization of specific early genes in fibroblasts. J Biol Chem. 2005; 280(11):10253-63. DOI: 10.1074/jbc.M413806200. View

20.

Thomas S, Brugge J . Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997; 13:513-609. DOI: 10.1146/annurev.cellbio.13.1.513. View