Retinoic acid induces selective expression of phosphoinositide 3-kinase gamma in myelomonocytic U937 cells

Retinoic acid provokes growth inhibition and differentiation of the human l eukemic cell line U937 to macrophage-like cells. We report that treatment o f U937 cells with all-trans retinoic acid (ATRA), but not the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, results in an increased gene expressi on of the phosphoinositide 3-kinase (P13K) species P13K gamma, P13K gamma e xpression was transcriptionally elevated, indicating that the P13K gamma ge ne may be a direct target for ATRA, In contrast to its effect on P13K gamma expression, ATRA did neither affect the levels of the P13K species beta an d delta nor the adapter proteins p85 and p101. Enhanced expression by ATRA of P13K gamma correlated with an increase of P13K lipid kinase activity. Ad ditionally, ATRA induced significant and lasting stimulation of mitogen-act ivated protein kinase/Erk2 activity. This effect was sensitive to the P13K inhibitors wortmannin or LY294002 and, therefore, attributed to the upregul ation of P13K gamma expression, Our findings suggest that sustained MAPK ac tivation via P13K gamma precedes ATRA -dependent differentiation or growth inhibition.