Staurosporine stimulates progesterone production by bovine placental cells.
Progesterone (P4) production by the bovine placenta differs from that of other steroidogenic tissue in two important respects: 1) it is calcium-dependent but cyclic nucleotide-independent and 2) it is suppressed by an endogenous inhibitor for most of the life span of the placenta. This natural refractory state of the placenta can be overcome in in vitro incubations of fetal cotyledon cells by agents that increase intracellular calcium (3-isobutylmethylxanthine [MIX], calcium ionophore (A23187), addition of substrate (pregnenolone, hydroxycholesterol), and stimulators of protein kinase C (PKC) such as phorbol ester (TPA). We therefore tested, in cultures of cotyledonary cells, two compounds that have been reported to inhibit protein kinases: 1) staurosporine (STA), an inhibitor of PKC, cAMP-dependent kinase, tyrosine kinase (TK), and the epidermal growth factor (EGF) receptor TK, and 2) genistein, an inhibitor of TK. It was found that STA stimulated steroidogenesis in a dose-dependent manner in both the absence and presence of added calcium. STA (10(-9) M) stimulated at least a twofold increase in P4 production by cultured fetal cotyledon cells throughout the first half of gestation (50-130 days). EGF was also found to cause a twofold stimulation of P4 production, and the effect was additive to that of STA. Both basal and EGF- or STA-stimulated production were inhibited by genistein. In contrast, two inhibitors of PKC and PKA (H-7, H-8) had no effect on P4 production. We conclude that STA-induced steroidogenesis in the bovine placenta is not related to its reported ability to inhibit PKC, TK, or EGF receptor TK.
Shemesh
M
M
Department of Hormone Research, Kimron Veterinary Institute, Bet Dagan, Israel.
Harel-Markowitz
E
E
Gurevich
M
M
Shore
L S
LS
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002417:Cattle / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D019311:Staurosporine
D000470:Alkaloids; D007529:Isoflavones; D047428:Protein Kinase Inhibitors; D011374:Progesterone; D003513:Cycloheximide; D019833:Genistein; D011494:Protein Kinases; D019311:Staurosporine; D002118:Calcium