The Src tyrosine kinase pathway regulates thecal CYP17 expression and androstenedione secretion.
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.
Chaturvedi
Gaurav
G
Department of Molecular and Integrative Physiology, The Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Arai
Koji
K
Terranova
Paul F
PF
Roby
Katherine F
KF
D000735:Androstenedione / Q000378:metabolism*; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism; D013799:Theca Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
C412373:AG 1879; D005419:Flavonoids; D010750:Phosphoproteins; D011743:Pyrimidines; D054339:Steroidogenic Factor 1; D000098682:Steroidogenic Acute Regulatory Protein; D005576:Colforsin; D000735:Androstenedione; D000242:Cyclic AMP; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D019061:src-Family Kinases; D048369:MAP Kinase Kinase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one