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Suppression of Tumor Growth and Cell Proliferation by p13 II, a Mitochondrial Protein of Human T Cell Leukemia Virus Type 1
Micol Silic-Benussi, Ilaria Cavallari, Tatiana Zorzan, Elisabetta Rossi, Hajime Hiraragi, Antonio Rosato, Kyoji Horie, Daniela Saggioro, Michael D. Lairmore, Luc Willems, Luigi Chieco-Bianchi, Donna M. D'Agostino, Vincenzo Ciminale and Robert C. Gallo
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 17 (Apr. 27, 2004), pp. 6629-6634
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3372134
Page Count: 6
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Human T cell leukemia virus type 1 encodes an "accessory" protein named p13 II that is targeted to mitochondria and triggers a rapid flux of K+ and Ca2+ across the inner membrane. In this study, we investigated the effects of p13 II on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13 II significantly reduced the incidence and growth rate of tumors arising from c-myc and Ha-ras-cotransfected rat embryo fibroblasts. Consistent with these findings, HeLa-derived cell lines stably expressing p13 II exhibited markedly reduced tumorigenicity, as well as reduced proliferation at high density in vitro. Mixed culture assays revealed that the phenotype of the p13 II cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13 II cell lines exhibited an enhanced response to Ca2+-mediated stimuli, as measured by increased sensitivity to C2-ceramide-induced apoptosis and by cAMP-responsive element-binding protein (CREB) phosphorylation in response to histamine. p13 II-expressing Jurkat T cells also exhibited reduced proliferation, suggesting that the protein might exert similar effects in T cells, the primary target of HTLV-1 infection. These findings provide clues into the function of p13 II as a negative regulator of cell growth and underscore a link between mitochondria, Ca2+ signaling, and tumorigenicity.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences