Received for publication December 13, 2005.
Revised November 13, 2006.
Accepted for publication November 14, 2006.

RanGAP-Mediated Nuclear Protein Import in Vascular Smooth Muscle Cells is Augmented by Lysophosphatidylcholine

Abstract

The intracellular mechanism responsible for the mitogenic effects of lysophosphatidylcholine (LPC) is unclear. There are many ways to alter cell proliferation and gene expression. Import of proteins from the cytoplasm into the cell nucleus is integral to the regulation of gene expression. We hypothesized that LPC exerts its intracellular effects through alterations in nuclear protein import. Rabbit aortic smooth muscle cells incubated with LPC induced a significant increase in cell proliferation in both quiescent cells (63.2 ± 6.48% of control) and cells grown in 1%FBS (28.3 ± 7.35% of control). Vascular smooth muscle cells were pre-incubated with LPC then microinjected with a marker protein for nuclear import. A significant stimulation of nuclear protein transport was observed. Using a conventional nuclear protein import assay in permeabilized cells, a significant stimulation of import (72.3 ± 5.2% of control) was again observed when the cytosolic nuclear import cocktail was treated with LPC. This effect was not observed with other lysophosphatidyl species. LPC also activated the ERK1/2 MAPK pathway and this was blocked by PD98059, which inhibits the activation of ERK 1/2. The stimulation of nuclear import was also blocked by PD98059. LPC-induced MAPK activation augmented GTP hydrolysis by RanGAP, a RanGTPase activating protein and a critical regulatory component of nuclear protein import, and this stimulation was again blocked by PD98059. We conclude that LPC alters gene expression and cell proliferation through striking effects on nuclear protein import via a MAP kinase-induced activation of RanGAP. This may play an important role in cancer and atherosclerosis and other disorders involving accelerated cell growth/proliferation.

Key words: Phospholipase A2's, G protein regulation, Membrane targets, Angiogenesis, Ischemia/Reperfusion, Tissue hypertrophy

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