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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Disruption of -actinin-integrin interactions at focal adhesions renders osteoblasts susceptible to apoptosis

Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 14 March 2006 ; accepted in final form 18 June 2006

Maintenance of bone structural integrity depends in part on the rate of apoptosis of bone-forming osteoblasts. Because substrate adhesion is an important regulator of apoptosis, we have investigated the role of focal adhesions in regulating bone cell apoptosis. To test this, we expressed a truncated form of -actinin (ROD-GFP) that competitively displaces endogenous -actinin from focal adhesions, thus disrupting focal adhesions. Immunofluorescence and morphometric analysis of vinculin and tyrosine phosphorylation revealed that ROD-GFP expression dramatically disrupted focal adhesion organization and reduced tyrosine phosphorylation at focal adhesions. In addition, Bcl-2 protein levels were reduced in ROD-GFP-expressing cells, but caspase 3 cleavage, poly(ADP-ribose) polymerase cleavage, histone H2A.X phosphorylation, and cytotoxicity were not increased due to ROD-GFP expression alone. Increases in both ERK and Akt phosphorylation were also observed in ROD-GFP-expressing cells, although inhibition of either ERK or Akt individually or together failed to induce apoptosis. However, we did find that ROD-GFP expression sensitized, whereas -actinin-GFP expression protected, cells from TNF--induced apoptosis. Further investigation revealed that activation of TNF--induced survival signals, specifically Akt phosphorylation and NF-B activation, was inhibited in ROD-GFP-expressing cells. The reduced expression of antiapoptotic Bcl-2 and inhibited survival signaling rendered ROD-GFP-expressing cells more susceptible to TNF--induced apoptosis. Thus we conclude that -actinin plays a role in regulating cell survival through stabilization of focal adhesions and regulation of TNF--induced survival signaling.

tumor necrosis factor-; survival; cytoskeleton; nuclear factor-B

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