The balance between proliferation and apoptosis of mesangial cells is a critical component of proliferative glomerulonephritis. The regulation of cell proliferation and apoptosis is linked at the level of the cell cycle (Shankland SJ. Kidney Int 52: 294-308, 199). cPLA2-interacting protein (PLIP), the Tip60 splice variant, interacts with cPLA2 and enhances the susceptibility of renal mesangial cells to serum deprivation-induced apoptosis (Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, and Bonventre JV. Mol Cell Biol 21: 4470-4481, 2001). We report that adenoviral-driven PLIP expression results in enhanced apoptosis of non-serum-deprived mesangial cells associated with a marked decrease in G0/G1 phase cells. The effect of PLIP on the cell cycle may be independent of its interaction with cPLA2 because a mutation of PLIP that does not interact with cPLA2 also causes a decrease in G0/G1 cells. Endogenous PLIP and Tip60 protein levels are increased in cells exposed to injurious stimuli including X-irradiation and H2O2, but the intracellular localization of the splice variants may differ. Whereas PLIP localizes in the nucleus of all mesangial cells, Tip60 localizes in the cytosol of untreated mesangial cells and of cells exposed to low concentrations (50-200 microM) of H2O2. Tip60 is targeted to the nucleus of cells exposed to high concentrations (1-2 mM) of H2O2. We conclude that PLIP may cause cells to exit from the cell cycle after the S phase and may function as part of a G2/M checkpoint mechanism. Tip60 splice variants may function in both cytosolic and nuclear signaling pathways in mesangial cells.