Identification of a hTid-1 mutation which sensitizes gliomas to apoptosis.
Human Tid-1 (hTid-1) is a DnaJ chaperone protein with homology to the Drosophila tumor suppressor Tid56. We report the first case of a tumor-associated mutation at the human TID1 locus, which was identified in the SF767 glioma cell line giving rise to aberrantly high levels of a hTid-1(L) mutant variant. In this study, we set out to determine whether this change in hTid-1 status influences the response of glioma cells to adenoviral (Ad)-mediated delivery of the two major isoforms of TID1, hTid-1(L) and hTid-1(S). Ad-hTid-1(S) induced apoptosis in hTid-1 mutant SF767 cells, while causing growth arrest in wild-type hTid-1-expressing U373 and U87 cells. By contrast, Ad-hTid-1(L) infection had no apparent effect on glioma cell growth. The apoptosis induced by hTid-1(S) was accompanied by mitochondrial cytochrome C release and caspase activation and blocked by stable overexpression of Bcl-X(L). Our findings suggest that the status of hTid-1 in gliomas may contribute to their susceptibility to cell death triggers.
Trentin
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Faculty of Health Sciences, McMaster University, Hamilton, Ont., Canada L8N 3Z5.
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Wu
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Tang
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Rozakis-Adcock
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D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003574:Cytochrome c Group / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D005910:Glioma; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D019476:Insect Proteins / Q000235:genetics; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones / Q000235:genetics*; D008970:Molecular Weight; D009154:Mutation; D011419:Propidium; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C093721:CG5504 protein, Drosophila; D003574:Cytochrome c Group; C120664:DNAJA3 protein, human; D029721:Drosophila Proteins; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D019476:Insect Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011419:Propidium; D020169:Caspases