Molecular mechanism of tumorigenesis in mice transgenic for the human T cell leukemia virus Tax gene.
The infection by human T lymphotropic virus type I is associated with adult T cell leukemia and several inflammatory degenerative disorders, including tropical spastic paraparesis. To investigate the role of the Tax protein in the development of diseases linked to human T lymphotropic virus type I infection, we generated two lines of transgenic mice carrying the tax gene under the control of the viral promoter. The expression of the transgene was low in these mice and was restricted to the central nervous system and testis. Mice from both lines developed various types of tumors, including fibrosarcomas and adenocarcinomas. Tax was expressed at a high level in fibrosarcomas and in cell lines derived from these tumors. In tumor-derived cells, the expression of Tax led to an increased degradation of IkappaB alpha and IkappaB beta and caused stable nuclear translocation of nuclear factor-kappaB. This translocation was essential for cell proliferation, as shown by expressing a nondegradable form of IkappaBbeta in these cells. Therefore, Tax-induced cell transformation in mice correlates with the degradation of IkappaB alpha and IkappaB beta and with the constitutive activation of NF-kappaB.
ERS CNRS 572, Institut Pasteur, 28 rue du Dr. Roux, 75724, Paris Cedex 15, France.
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Coscoy
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Gonzalez-Dunia
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Tangy
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Brahic
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Ozden
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000821:virology*; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D007739:L Cells; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000502:physiology; D013623:Tail; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016356:Gene Products, tax; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051841:Transcription Factor RelB