Submitted on February 14, 2006
Revised on April 26, 2006
Accepted on May 1, 2006
Regulation of de novo phosphatidylinositol synthesis
Samer J. Nuwayhid, Martha Vega, Paul D. Walden, and Marie E. Monaco
Physiology & Neuroscience, NYU School of Medicine, New York, NY 10010
Corresponding Author: mem6{at}nyu.edu
Mechanisms that function to regulate the rate of de novo phosphatidylinositol (PtdIns) in mammalian cells have not been elucidated. In the present study, we characterize the effect of phorbol ester treatment on de novo PtdIns synthesis in C3A human hepatoma cells. Incubation of cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA) initially (1-6 hours) results in a decrease in precursor incorporation into PtdIns; however, at later times (18-24 hours), a marked increase is observed. TPA-induced glucose uptake from the medium is not required for observation of stimulation of PtdIns synthesis, since the effect is apparent in glucose-free medium. Inhibition of the activation of arachidonic acid substantially blocks synthesis of PtdIns, while having no effect on synthesis of phosphatidylcholine (PtdCho). Increasing the concentration of cellular phosphatidic acid (PtdOH) by blocking its conversion to diacylglycerol (DAG), on the other hand, enhances synthesis of PtdIns while inhibiting synthesis of PtdCho. The TPA-induced stimulation of PtdIns synthesis is not the result of the concomitant TPA-induced G1 arrest, since G1 arrest induced by mevastatin has no effect on PtdIns synthesis. Inhibition of protein kinase C (PKC) activity blocks the stimulatory action of TPA on de novo synthesis of PtdIns, but has no effect on TPA-induced inhibition. Potential sites of enzymatic regulation are discussed.
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