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Retinoic Acid Induces Selective Expression of Phosphoinositide 3-Kinase in Myelomonocytic U937 Cells

Research Unit "Molecular Cell Biology" [R. B., T. B., A. B., R. W.] and Institute for Biochemistry II [R. B., R. K.], Medical Faculty, Friedrich-Schiller-University, D-07747 Jena, Germany

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 PI3K. PI3K expression was transcriptionally elevated, indicating that the PI3K gene may be a direct target for ATRA. In contrast to its effect on PI3K expression, ATRA did neither affect the levels of the PI3K species ß and nor the adapter proteins p85 and p101. Enhanced expression by ATRA of PI3K 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 up-regulation of PI3K expression. Our findings suggest that sustained MAPK activation via PI3K precedes ATRA-dependent differentiation or growth inhibition.

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