Suppression of tumor growth and cell proliferation by p13 super(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 super(II) that is targeted to mitochondria and triggers a rapid flux of K super(+) and Ca super(2+) across the inner membrane. In this study, we investigated the effects of p13 super(II) on tumorigenicity in vivo and on cell growth in vitro. Results showed that p13 super(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 super(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 super(II) cell lines was dominant over that of control lines and was mediated by a heat-labile soluble factor. The p13 super(II) cell lines exhibited an enhanced response to Ca super(2+)-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 super(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 super(II) as a negative regulator of cell growth and underscore a link between mitochondria, Ca super(2+) signaling, and tumorigenicity.