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Journal of Lipid Research, Vol. 45, 1555-1564, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Phosphatidylinositol transfer protein regulates growth and apoptosis of NIH3T3 cells

Martijn Schenning^*,1, Claudia M. van Tiel^*, Daniëlle van Manen^*, Jord C. Stam, Barend M. Gadella, Karel W. A. Wirtz^* and Gerry T. Snoek^*

^* Center for Biomembranes and Lipid Enzymology, Department of Lipid Biochemistry, Institute of Biomembranes, Utrecht University, 3584 CM Utrecht, The Netherlands
Utrecht Institute of Biomembranes, Department of Molecular Cell Biology, Utrecht University, 3584 CM Utrecht, The Netherlands
Department of Farm Animal Health, Utrecht University, 3584 CM Utrecht, The Netherlands

¹ To whom correspondence should be addressed. e-mail: m.schenning{at}chem.uu.nl

Mouse fibroblast cells overexpressing phosphatidylinositol transfer protein [PI-TP; sense PI-TP (SPI) cells] show a significantly increased rate of proliferation and an extreme resistance toward ultraviolet- or tumor necrosis factor--induced apoptosis. The conditioned medium (CM) from SPI cells or the neutral lipid extract from CM stimulated the proliferation of quiescent wild-type NIH3T3 cells. CM was also highly effective in increasing resistance toward induced apoptosis in both wild-type cells and the highly apoptosis-sensitive SPIß cells (i.e., wild-type cells overexpressing PI-TPß). CM from SPI cells grown in the presence of NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, expressed a diminished mitogenic and antiapoptotic activity. This strongly suggests that at least one of the bioactive factor(s) is an eicosanoid. In accordance, SPI cells express enhanced levels of COX-1 and COX-2. The antiapoptotic activity of CM from SPI cells tested on SPIß cells was inhibited by 50% by pertussis toxin and suramin as well as by SR141716A, a specific antagonist of the cannabinoid 1 receptor. These inhibitors had virtually no effect on the COX-2-independent antiapoptotic activity of CM from SPI cells..

The latter results imply that PI-TP mediates the production of a COX-2-dependent eicosanoid that activates a G-protein-coupled receptor, most probably a cannabinoid 1-like receptor.

Abbreviations: CB1, cannabinoid 1; CM, conditioned medium; COX, cyclooxygenase; DBB, DMEM/bicarbonate containing 0.1% BSA; GPCR, G-protein-coupled receptor; NCS, newborn calf serum; PGE₂, prostaglandin E₂; PI-TP, phosphatidylinositol transfer protein; PLA₂, phospholipase A₂; PVA, polyvinyl alcohol; SPI, sense PI-TP; UV, ultraviolet; wtNIH3T3, wild-type NIH3T3 cells

Supplementary key words cyclooxygenase 2 • proliferation • eicosanoids

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