Block of a mitochondrial-mediated apoptotic pathway in Tax-expressing murine fibroblasts.
Although the viral transactivator Tax has been established as an essential effector of HTLV-I-mediated oncogenesis, its exact role(s) in the pathogenesis of HTLV-I-associated diseases, which include both a neurodegenerative pathology and leukemia/lymphoma, remains to be clarified. It was recently advanced that dysregulation of the apoptotic process can lead to pathophysiological changes which result in either degenerative diseases or cancer. As the apoptotic potential of Tax is still debated, we addressed this question by testing the susceptibility of Tax(+) and Tax(-) murine fibroblasts to apoptosis under conditions of growth factor withdrawal or treatment with TNFalpha, which trigger apoptosis through different pathways, i.e., mitochondrial and receptor-mediated pathways, respectively. Results showed that Tax-expressing cells are protected from apoptotic death induced by serum deprivation but are sensitive to TNFalpha-mediated apoptosis, suggesting that Tax expression has different effects on cell death, depending on the apoptotic stimulus used. Analysis of the mechanism(s) involved in the resistance to serum depletion-induced apoptosis indicated that Tax(+) cells do not undergo release of cytochrome c from the mitochondrial intermembrane space or redistribution of Bax from the cytosol to mitochondria, two phenomena critical to the mitochondrial apoptotic pathway.
Saggioro
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D
Department of Oncology and Surgical Sciences-Oncology Section, IST, Viral and Molecular Oncology Section, University of Padova, Via Gattamelata 64, Padua, 35128, Italy. d.saggioro@unipd.it
Barp
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Chieco-Bianchi
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D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism*; D016356:Gene Products, tax / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013997:Time Factors; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D003574:Cytochrome c Group; D016356:Gene Products, tax; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D003513:Cycloheximide