Src tyrosine kinase pathway regulates thecal CYP17 expression and androstenedione secretion

• Published in: Molecular and cellular biochemistry Vol. 318; no. 1-2; pp. 191 - 200
• Main Authors: Chaturvedi, Gaurav, Arai, Koji, Terranova, Paul F, Roby, Katherine F
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.11.2008; Springer US; Springer Nature B.V
• Subjects: Androstenedione - secretion; Animals; Biochemistry; Biomedical and Life Sciences; Cardiology; Cholesterol Side-Chain Cleavage Enzyme - genetics; Cholesterol Side-Chain Cleavage Enzyme - metabolism; Colforsin - pharmacology; Cyclic AMP - metabolism; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Female; Flavonoids - pharmacology; Gene expression; Kinases; Life Sciences; MAP Kinase Kinase 1 - antagonists & inhibitors; Medical Biochemistry; Mice; Mice, Inbred C57BL; Oncology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Promoter Regions, Genetic; Proteins; Pyrimidines - pharmacology; Ribonucleic acid; RNA; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Steroid 17-alpha-Hydroxylase - genetics; Steroid 17-alpha-Hydroxylase - metabolism; Steroidogenic Factor 1 - genetics; Steroidogenic Factor 1 - metabolism; Theca Cells - drug effects; Theca Cells - enzymology; Theca Cells - secretion; SF-1; CYP17; MAP kinase; Androstenedione; Src tyrosine kinase; Theca
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-008-9871-9

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.