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Deficiency Causes Resistance to Tumor Necrosis Factor--Induced Cell Death via Reduced Activation of the Phosphatidylinositide 3-kinase/Akt Pathway
1 Division of Translational Research, Clinical Research Institute, Kyoto National Hospital, Kyoto, Kyoto, Japan
2 Department of Cardiology, National Cardiovascular Center, Suita, Osaka, Japan
3 Department of Pharmacology, National Cardiovascular Center, Suita, Osaka, Japan
4 Department of Cardiovascular Medicine, Kyoto University, Kyoto, Kyoto, Japan
* To whom correspondence should be addressed. E-mail: kohono{at}kuhp.kyoto-u.ac.jp.
We used retrovirus insertion-mediated random mutagenesis to generate tumor necrosis factor-
(TNF-)-resistant lines from L929 cells. Using this approach, we
discovered that caveolin-1 is required for TNF--induced cell death in L929 cells. The need for caveolin-1 in TNF--induced cell death was confirmed by the restoration of sensitivity to TNF- after ectopic reconstitution of caveolin-1/
expression. This caveolin-1-mutated line was also resistant to H2O2 and staurosporine, but not to
lonidamine. HepG2 cells are known to lack endogenous caveolins. HepG2 cells stably transfected with caveolin-1/ were found to be much more sensitive to TNF- than either parental cells transfected with caveolin-1 or parental cells transfected with an
empty vector. In contrast to its extensively documented antiapoptotic effect, the elevated activity of Akt appears to be important in sensitizing caveolin-1-expressing cells to TNF-, since pretreatment of cells with the phosphatidylinositide 3-kinase (PI3K) inhibitor LY294002 or wortmannin completely blocked PI3K activation and markedly
improved the survival of TNF--treated L929 cells. The survival rates of caveolin-1-normal and caveolin-1]-deficient L929 cells were comparable after treatment with PI3K inhibitor and TNF-. Similar results were obtained with HepG2 cells that stably expressed caveolin-1/ or and parental cells transfected with an empty vector. In summary, our results indicate that caveolin-1 preferentially sensitizes L929 cells to TNF- through the activation of a PI3K/Akt signaling pathway.
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