Wortmannin, an inhibitor of phosphatidyl-inositol 3-kinase, induces oocyte maturation through a MPF-MAPK-dependent pathway.
Wortmannin has been shown to be a non-competitive and irreversible inhibitor of PI3 kinase. For this reason, it has attracted considerable interest and it has been used, as a selective inhibitor of the PI3 kinase, for the study of signal transduction pathways in different systems including Xenopus oocytes. We show here that wortmannin itself is able to induce meiotic maturation at doses slightly higher that those required for complete inhibition of PI3 kinase. This effect was shown to be independent of the ability to inhibit PI3K since another unrelated PI3K inhibitor, LY294002, was unable to induce oocyte maturation at inhibitory concentrations for PI3 kinase. The mechanism for wortmannin-induced maturation involves the activation of maturation promoting factor (MPF) and MAP kinase activities in a time course that preceded the appearance of germinal vesicle breakdown. Thus, the pathway activated by wortmannin directly or indirectly affects other protein or proteins, besides PI3 kinase, responsible for its activity. This new target is placed independently or downstream of the PI3 kinase inhibition and upstream of protein synthesis. Moreover, the inhibition of either MPF or cAMP phosphodiesterase blocks wortmannin-induced maturation. We conclude that wortmannin may be a valuable tool for the study of the pathway leading to mitotic maturation of oocytes, but cannot be used as a specific PI3 kinase inhibitor.
Carnero
A
A
Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain.
Lacal
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JC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D016200:Maturation-Promoting Factor / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin; D014982:Xenopus laevis
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C001020:N(6),N(6)-dimethyladenine; D003513:Cycloheximide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016200:Maturation-Promoting Factor; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000225:Adenine; D015056:1-Methyl-3-isobutylxanthine; D000077191:Wortmannin