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 Ca 2؉ 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 Ca 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 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, Ca 2؉ signaling, and tumorigenicity.apoptosis ͉ calcium signaling ͉ tumorigenicity ͉ retrovirus H uman T cell leukemia virus type 1 (HTLV-1) possesses a complex genome that codes for Gag, Pol, Env, Tax, Rex, and a number of ''accessory'' proteins (1-4). Although the function of the accessory proteins has not yet been elucidated completely, they elicit an immune response in HTLV-1 infected individuals (5) and are required for efficient viral propagation in an animal model (6).One of the HTLV-1 accessory proteins, p13 II , accumulates in mitochondria by means of an amphipathic mitochondrial targeting signal and disrupts mitochondrial morphology (7). Biochemical analyses showed that p13 II is inserted in the inner mitochondrial membrane and alters mitochondrial conductance to Ca 2ϩ and K ϩ , leading to swelling and collapse of inner mitochondrial membrane potential (8).These effects suggest that p13 II might alter key mitochondrial functions such as energy production, redox status, and apoptosis, which could in turn disrupt the balance between cell death and proliferation. In this study, we investigated the impact of p13 II on cell growth in vitro and tumor growth in vivo by using the rat embryo fibroblast (REF) transformation model and cell lines expressing p13 II . Results showed that p13 II -expressing cells exhibit reduced tumorigenicity in vivo and slower proliferation at high density in vitro. p13 II -expressing cells also display perturbations in signal transduction pathways depending on Ca 2ϩ homeostasis. Materials and MethodsGeneration of HeLa Tet-On Cell Lines Expressing p13 II . The doxycyclininducible p13 II expression plasmid pTRE-p13 II -AU1 was constructed by inse...
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