Protein Kinase A-Independent cAMP Stimulation of Progesterone in a Luteal Cell Model Is Tyrosine Kinase Dependent but Phosphatidylinositol-3-Kinase and Mitogen-Activated Protein Kinase Independent

• Published in: Biology of reproduction Vol. 77; no. 1; pp. 147 - 155
• Main Authors: Needle, Elie, Piparo, Kathy, Cole, Donna, Worrall, Carolyn, Whitehead, Ian, Mahon, Gwen, Goldsmith, Laura T
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction, Inc 01.07.2007; Society for the Study of Reproduction
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Animals; Biological and medical sciences; Cell Line; Corpus Luteum - cytology; Corpus Luteum - metabolism; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Hormone metabolism and regulation; Mammalian female genital system; Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Progesterone - biosynthesis; Progesterone - genetics; Progesterone - metabolism; Protein-Tyrosine Kinases - metabolism; Rats; Vertebrates: reproduction; Rat; Progestagen; Ovary; Signal transduction; Reproduction; Luteal cell; Female genital system; Female; EC 2.7.1.112; EC 2.7.1.137; Enzyme; Transferases; corpus luteum function; Rodentia; Cyclic AMP; Mitogen-activated protein kinase; cAMP-dependent protein kinase; In vitro; 1-Phosphatidylinositol 3-kinase; Vertebrata; Mammalia; Corpus luteum; Models; Progesterone; female reproductive tract
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.106.053918

Comprehensive understanding of the cellular mechanisms utilized by luteal cells in response to extracellular hormonal signals resulting in the normal synthesis and secretion of their steroid and peptide products has yet to be achieved. Previous studies have established that cAMP functions as a second messenger in mediating gonadotropin stimulated luteal progesterone secretion. Classically, increased intracellular concentrations of cAMP result in activation of protein kinase A (PKA), which in turn phosphorylates gene regulatory transcription factors. Recent studies demonstrate that non-PKA mediated actions of cAMP exist, yet the mechanisms are not well understood. In addition to gonadotropic hormones, such growth factors as insulin, insulin-like growth factor 1, and epidermal growth factor have been shown to modulate luteal steroid hormone synthesis and steroidogenic enzyme expression as either independent effects or via amplification or modulation of the action of gonadotropic hormones or cAMP. Thus, mechanisms independent of cAMP and also downstream to cAMP that do not involve PKA are likely to be important in steroidogenesis in mammalian cells. The present studies were performed to help define the cellular mediators involved in cAMP-stimulated progesterone expression. Our data demonstrate that, in an in vitro steroidogenic cell model, 1) cAMP-stimulated progesterone occurs in a manner that is independent of PKA, 2) neither phosphatidylinositol-3-kinase nor mitogen-activated protein kinase are involved in PKA-independent cAMP-stimulated progesterone production, 3) tyrosine kinase activity does mediate cAMP-stimulated progesterone production, and 4) cAMP directly activates the Ras protein. These data suggest novel mediators of cAMP-stimulated progesterone production.