Retinoic acid induces selective expression of phosphoinositide 3-kinase gamma in myelomonocytic U937 cells.
Retinoic acid provokes growth inhibition and differentiation of the human leukemic cell line U937 to macrophage-like cells. We report that treatment of U937 cells with all-trans retinoic acid (ATRA), but not the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, results in an increased gene expression of the phosphoinositide 3-kinase (PI3K) species PI3Kgamma. PI3Kgamma expression was transcriptionally elevated, indicating that the PI3Kgamma gene may be a direct target for ATRA. In contrast to its effect on PI3Kgamma expression, ATRA did neither affect the levels of the PI3K species beta and delta nor the adapter proteins p85 and p101. Enhanced expression by ATRA of PI3Kgamma correlated with an increase of PI3K lipid kinase activity. Additionally, ATRA induced significant and lasting stimulation of mitogen-activated protein kinase/Erk2 activity. This effect was sensitive to the PI3K inhibitors wortmannin or LY294002 and, therefore, attributed to the upregulation of PI3Kgamma expression. Our findings suggest that sustained MAPK activation via PI3Kgamma precedes ATRA -dependent differentiation or growth inhibition.
Research Unit Molecular Cell Biology, Medical Faculty, Friedrich-Schiller-University, Jena, Germany.
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Baier
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Bondeva
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Klinger
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Bondev
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Wetzker
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D020298:U937 Cells
D007527:Isoenzymes; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D013755:Tetradecanoylphorbol Acetate