The Src tyrosine kinase pathway regulates thecal CYP17 expression and androstenedione secretion

Mol Cell Biochem. 2008 Nov;318(1-2):191-200. doi: 10.1007/s11010-008-9871-9. Epub 2008 Jul 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenedione / metabolism*
  • Animals
  • 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
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic
  • Pyrimidines / pharmacology
  • 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 / metabolism*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • AG 1879
  • Flavonoids
  • Phosphoproteins
  • Pyrimidines
  • Steroidogenic Factor 1
  • steroidogenic acute regulatory protein
  • Colforsin
  • Androstenedione
  • Cyclic AMP
  • Steroid 17-alpha-Hydroxylase
  • Cholesterol Side-Chain Cleavage Enzyme
  • src-Family Kinases
  • MAP Kinase Kinase 1
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one