Human T-cell leukemia virus type 1 tax dysregulates beta-catenin signaling.
Dysregulation of beta-catenin signaling has been implicated in the malignant transformation of cells. However, the role of beta-catenin in the human T-cell leukemia virus type 1 (HTLV-1)-induced transformation of T cells is unknown. Here we found that beta-catenin protein was overexpressed in the nucleus and that beta-catenin-dependent transcription was significantly enhanced in Tax-positive HTLV-1-infected T-cell lines compared to that in Tax-negative HTLV-1-infected T-cell lines. Transfection with beta-catenin-specific small interfering RNA inhibited the growth of the Tax-positive HTLV-1-infected T-cell line HUT-102. Transient transfection of Tax appeared to enhance beta-catenin-dependent transcription by stabilizing the beta-catenin protein via activation of the cyclic AMP (cAMP) response element-binding protein. HTLV-1-infected T-cell lines overexpressing beta-catenin also showed increased Akt activity via Tax activation of the cAMP response element-binding protein, resulting in the phosphorylation and inactivation of glycogen synthase kinase 3beta, which phosphorylates beta-catenin for ubiquitination. The phosphatidylinositol 3-kinase inhibitor LY294002 reduced beta-catenin expression in Tax-positive T-cell lines, and inactivation of glycogen synthase kinase 3beta by lithium chloride restored beta-catenin expression in Tax-negative T-cell lines. Finally, we showed that dominant-negative Akt inhibited Tax-induced beta-catenin-dependent transcription. These results indicate that Tax activates beta-catenin through the Akt signaling pathway. Our findings suggest that activation of beta-catenin by Tax may be important in the transformation of T cells by HTLV-1 infection.
Tomita
Mariko
M
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Kikuchi
Akira
A
Akiyama
Tetsu
T
Tanaka
Yuetsu
Y
Mori
Naoki
N
D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D016355:Genes, pX; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004279:DNA, Viral; D016356:Gene Products, tax; D061988:Proteasome Inhibitors; D051820:TCF Transcription Factors; D051176:beta Catenin; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt