Suppression of tumor growth and cell proliferation by p13^II, a mitochondrial protein of human T cell leukemia virus type 1

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.