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Vol. 15, Issue 3, 1273-1286, March 2004

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Tumor Necrosis Factor- Promotes Survival of Opossum Kidney Cells via Cdc42-induced Phospholipase C-1 Activation and Actin Filament Redistribution

Department of Biochemistry, School of Medicine, University of Crete, GR-71110 Heraklion, Greece

Submitted July 14, 2003; Revised November 3, 2003; Accepted November 17, 2003
Monitoring Editor: Carl-Henrik Heldin

Although the renal proximal tubular epithelial cells are targeted in a variety of inflammatory diseases of the kidney, the signaling mechanism by which tumor necrosis factor (TNF)- exerts its effects in these cells remains unclear. Here, we report that TNF- elicits antiapoptotic effects in opossum kidney cells and that this response is mediated via actin redistribution through a novel signaling mechanism. More specifically, we show that TNF- prevents apoptosis by inhibiting the activity of caspase-3 and this effect depends on actin polymerization state and nuclear factor-B activity. We also demonstrate that the signaling cascade triggered by TNF- is governed by the phosphatidylinositol-3 kinase, Cdc42/Rac1, and phospholipase (PLC)-1. In this signaling cascade, Cdc42 was found to be selectively essential for PLC-1 activation, whereas phosphatidylinositol-3,4,5-triphosphate alone is not sufficient to activate the phospholipase. Moreover, PLC-1 was found to associate in vivo with the small GTPase(s). Interestingly, PLC-1 was observed to associate with constitutively active (CA) Cdc42V12, but not with CA Rac1V12, whereas no interaction was detected with Cdc42(T17N). The inactive Cdc42(T17N) and the PLC-1 inhibitor U73122 prevented actin redistribution and depolymerization, confirming that both signaling molecules are responsible for the reorganization of actin. Additionally, the actin filament stabilizer phallacidin potently blocked the nuclear translocation of nuclear factor-B and its binding activity, resulting in abrogation of the TNF--induced inhibition of caspase-3. To conclude, our findings suggest that actin may play a pivotal role in the response of opossum kidney cells to TNF- and implicate Cdc42 in directly regulating PLC-1 activity.

^* Corresponding author. E-mail address: cstourn{at}med.uoc.gr.

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