Suppression of tumor growth and cell proliferation by p13II, 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 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.
Silic-Benussi
Micol
M
Department of Oncology and Surgical Sciences, University of Padua, Via Gattamelata 64, 35128 Padua, Italy.
Cavallari
Ilaria
I
Zorzan
Tatiana
T
Rossi
Elisabetta
E
Hiraragi
Hajime
H
Rosato
Antonio
A
Horie
Kyoji
K
Saggioro
Daniela
D
Lairmore
Michael D
MD
Willems
Luc
L
Chieco-Bianchi
Luigi
L
D'Agostino
Donna M
DM
Ciminale
Vincenzo
V
D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000378:metabolism / Q000502:physiology*
D017931:DNA Primers; D012191:Retroviridae Proteins; C072813:rof protein, Human T-lymphotropic virus 1