Abstract
Expression of the proto-oncogene c-myc stimulates cell proliferation in the presence of the appropriate survival factors and triggers apoptosis in their absence; this dual capacity ensures that cell growth is restricted to the correct paracrine environment and is thereby strictly controlled. Recently our laboratory demonstrated that c-Myc-induced apoptosis requires the CD95 death receptor pathway and that insulin-like growth factor (IGF-1) signalling suppresses this killing. To investigate further the links between c-Myc and IGF-1 pathways in CD95-induced apoptosis, we examined the effects of c-Myc and a downstream IGF-1 survival kinase, Akt, on killing mediated by CD95 and its recruited effector proteins (FADD and caspase-8). Here, we show that c-Myc activation does not exacerbate killing induced by FADD or pro-caspase-8, which narrows the point at which c-Myc exerts its action downstream of the interaction of CD95 with its ligand and upstream of FADD. We show further that activated Akt suppresses CD95-induced apoptosis and that Akt exerts its activity at a point downstream of FADD but upstream of caspase-8. These results restrict the possible mechanisms by which CD95-induced apoptosis is modulated by death signals and survival factors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Antibodies / pharmacology
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Apoptosis* / drug effects
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Arabidopsis Proteins*
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Blotting, Western
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Caspase 8
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Caspase 9
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Caspases / genetics
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Caspases / metabolism
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Cell Line
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Cell Survival / drug effects
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Culture Media, Serum-Free
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Fatty Acid Desaturases / antagonists & inhibitors
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Fatty Acid Desaturases / genetics
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Fatty Acid Desaturases / metabolism
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Mice
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Plant Proteins / antagonists & inhibitors
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Plant Proteins / genetics
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Plant Proteins / metabolism
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Protein Precursors / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-myc / metabolism*
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Proto-Oncogene Proteins*
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Rats
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Signal Transduction* / drug effects
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Sirolimus / pharmacology
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology
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Transfection
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fas Receptor / immunology
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fas Receptor / metabolism*
Substances
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Antibodies
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Arabidopsis Proteins
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Culture Media, Serum-Free
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Plant Proteins
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Protein Precursors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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fas Receptor
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Tamoxifen
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afimoxifene
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Fatty Acid Desaturases
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Fad7 protein, Arabidopsis
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Casp8 protein, mouse
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Casp8 protein, rat
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Casp9 protein, mouse
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Casp9 protein, rat
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Caspase 8
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Caspase 9
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Caspases
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Sirolimus