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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
16
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pubmed:dateCreated |
2006-4-17
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pubmed:abstractText |
Recent studies suggest that the aryl hydrocarbon receptor (AhR) modulates susceptibilities to some pro-apoptotic agents. AhR-containing murine hepatoma 1c1c7 cultures underwent apoptosis following exposure to tumor necrosis factor-alpha (TNFalpha) + cycloheximide (CHX). In contrast, Tao cells, an AhR-deficient variant of the 1c1c7 line, were refractory to this treatment. AhR sense/antisense transfection studies demonstrated that AhR contents influenced susceptibility to the pro-apoptotic effects of TNFalpha + CHX. 1c1c7 cells and all variants expressed comparable amounts of TNF receptor-1 and TRADD. However, no cell line expressed FADD, and consequently pro-caspase-8 was not activated. AhR content did not influence JNK and NF-kappaB activation. However, Bid and pro-caspase-9, -3, and -12 processing occurred only in AhR-containing cells. Analyses of cathepsin B and D activities in digitonin-permeabilized cultures and the monitoring of cathepsin B/D co-localization with Lamp-1 indicated that TNFalpha + CHX disrupted late endosomes/lysosomes in only AhR-containing cells. Stabilization of acidic organelles with 3-O-methylsphingomyelin inhibited TNFalpha + CHX-induced apoptosis. The cathepsin D inhibitor pepstatin A suppressed in vitro cleavage of Bid by 1c1c7 lysosomal extracts. It also delayed the induction of apoptosis and partially prevented Bid cleavage and the activation of pro-caspases-3/7 in cultures treated with TNFalpha + CHX. Similar suppressive effects occurred in cultures transfected with murine Bid antisense oligonucleotides. These studies showed that in cells where pro-caspase-8 is not activated, TNFalpha + CHX can initiate apoptosis through lysosomal disruption. Released proteases such as cathepsin D trigger the apoptotic program by activating Bid. Furthermore, in the absence of exogenous ligand, the AhR modulates lysosomal disruption/permeability.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3-O-methylsphingomyelin,
http://linkedlifedata.com/resource/pubmed/chemical/BH3 Interacting Domain Death...,
http://linkedlifedata.com/resource/pubmed/chemical/Casp8 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 8,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin B,
http://linkedlifedata.com/resource/pubmed/chemical/Cathepsin D,
http://linkedlifedata.com/resource/pubmed/chemical/Cycloheximide,
http://linkedlifedata.com/resource/pubmed/chemical/Digitonin,
http://linkedlifedata.com/resource/pubmed/chemical/L-Lactate Dehydrogenase,
http://linkedlifedata.com/resource/pubmed/chemical/Leucine,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Synthesis Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Aryl Hydrocarbon,
http://linkedlifedata.com/resource/pubmed/chemical/Sphingomyelins,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
21
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pubmed:volume |
281
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
10954-67
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:16446372-Animals,
pubmed-meshheading:16446372-Apoptosis,
pubmed-meshheading:16446372-BH3 Interacting Domain Death Agonist Protein,
pubmed-meshheading:16446372-Blotting, Western,
pubmed-meshheading:16446372-Carcinoma, Hepatocellular,
pubmed-meshheading:16446372-Caspase 8,
pubmed-meshheading:16446372-Caspases,
pubmed-meshheading:16446372-Cathepsin B,
pubmed-meshheading:16446372-Cathepsin D,
pubmed-meshheading:16446372-Cell Line, Tumor,
pubmed-meshheading:16446372-Cycloheximide,
pubmed-meshheading:16446372-Digitonin,
pubmed-meshheading:16446372-Dose-Response Relationship, Drug,
pubmed-meshheading:16446372-Endosomes,
pubmed-meshheading:16446372-L-Lactate Dehydrogenase,
pubmed-meshheading:16446372-Leucine,
pubmed-meshheading:16446372-Lysosomes,
pubmed-meshheading:16446372-Mice,
pubmed-meshheading:16446372-Microscopy, Fluorescence,
pubmed-meshheading:16446372-Models, Biological,
pubmed-meshheading:16446372-Models, Statistical,
pubmed-meshheading:16446372-Oligonucleotides,
pubmed-meshheading:16446372-Peptide Hydrolases,
pubmed-meshheading:16446372-Protein Synthesis Inhibitors,
pubmed-meshheading:16446372-Receptors, Aryl Hydrocarbon,
pubmed-meshheading:16446372-Sphingomyelins,
pubmed-meshheading:16446372-Time Factors,
pubmed-meshheading:16446372-Tumor Necrosis Factor-alpha
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pubmed:year |
2006
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pubmed:articleTitle |
Aryl hydrocarbon receptor modulation of tumor necrosis factor-alpha-induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8-independent.
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pubmed:affiliation |
Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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