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A more recent version of this article appeared on March 1, 2004
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Submitted on July 14, 2003
Revised on November 3, 2003
Accepted on November 17, 2003
promotes survival of OK cells via Cdc42-induced PLC-
1 activation and actin filament redistribution
1 Department of Biochemistry, School of Medicine, University of Crete, GR-71110 Heraklion, Greece
* Corresponding author. E-mail address: cstourn{at}med.uoc.gr.
Although the renal proximal tubular epithelial cells are targeted in a variety of inflammatory diseases of the kidney, the signaling mechanism by which TNF-
exerts its effects in these cells remains unclear. Here, we report that TNF- elicits antiapoptotic effects in OK (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 NF-
B activity. We also demonstrate that the signaling cascade triggered by TNF- is governed by the PI-3 kinase, Cdc42/Rac1 and PLC-
1. In this signaling cascade, Cdc42 was found to be selectively essential for PLC-1 activation while PI(3,4,5)P3 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 NF-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 OK cells to TNF- and implicate Cdc42 in directly regulating PLC-1 activity.
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