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Molecular and Cellular Biology, December 2001, p. 8276-8288, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8276-8288.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Resistance to Tumor Necrosis Factor-Induced Cell Death Mediated by PMCA4 Deficiency†

Koh Ono, Xiaofei Wang,Dagger and Jiahuai Han*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Received 28 June 2001/Returned for modification 20 August 2001/Accepted 12 September 2001

We used retrovirus insertion-mediated random mutagenesis to generate tumor necrosis factor (TNF)-resistant lines from L929 cells. Using this approach, we discovered that the plasma membrane calcium ATPase 4 (PMCA4) is required for TNF-induced cell death in L929 cells. Under basal conditions, PMCA4-deficient (PMCAmut) cells have a normal phenotype. However, stimulation with TNF induces an abnormal increase in the intracellular calcium concentration ([Ca2+]i). The substantially elevated [Ca2+]i caused resistance to TNF-induced cell death. We found that an increase in the total volume of acidic compartments (VAC), mainly constituted by lysosomes, is a common event in cell death caused by a variety of agonists. The increased [Ca2+]i in PMCAmut cells promoted lysosome exocytosis, which, at least in part, accounted for the inhibition of TNF-induced increase in VAC and cell death. Promoting lysosome exocytosis by calcium inhibited TNF-induced cell death in wild-type L929 cells, while inhibition of lysosome exocytosis or increase of VAC by sucrose restored the sensitivity of PMCAmut cells to TNF-induced cell death. Thus, increase of the volume of acidic compartment is a part of the cell death process, and the antideath effect of calcium is mediated, at least in part, by inhibition of the TNF-induced increase in VAC.

* Corresponding author. Mailing address: Department of Immunology IMM-32, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-8704. Fax: (858) 784-8665. E-mail: jhan{at}scripps.edu.

dagger This is publication no. 14231-IMM from the Department of Immunology, The Scripps Research Institute, La Jolla, Calif.

Dagger Present address: Avigen, Inc., Alameda, CA 94502.

Molecular and Cellular Biology, December 2001, p. 8276-8288, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8276-8288.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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