Abstract
In T lymphocytes, the role of Akt in regulating Fas/Fas ligand (FasL)-mediated apoptotic signaling and death is not clearly understood. In this study, we observed that inhibition of Akt causes enhanced expression of FasL mRNA and protein and increased death-inducing signaling complex (DISC) formation with Fas-associated death domain (FADD) and procaspase-8 recruitment. Also, caspase-8 was activated at the DISC with accompanying decrease in c-FLIPs expression. FasL neutralizing antibody significantly decreased apoptotic death in the Akt-inhibited T cells. Additionally, Akt inhibition-induced Fas signaling was observed to link to the mitochondrial pathway via Bid cleavage. Further, inhibition of caspase-8 activity effectively blocked the loss of mitochondrial membrane potential and DNA fragmentation, suggesting that DISC formation and subsequent caspase-8 activation are critical initiating events in Akt inhibition-induced apoptotic death in T lymphocytes. These data demonstrate yet another important survival function governed by Akt kinase in T lymphocytes, which involves the regulation of FasL expression and consequent apoptotic signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis / drug effects
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Apoptosis / physiology*
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BH3 Interacting Domain Death Agonist Protein
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / metabolism
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Caspase 8
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Caspases / metabolism*
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Chromones / pharmacology
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Down-Regulation
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Fas Ligand Protein
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Fas-Associated Death Domain Protein
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism*
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Jurkat Cells
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Membrane Glycoproteins / biosynthesis*
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Membrane Potentials
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Mitochondria / physiology
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Morpholines / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction
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T-Lymphocytes / metabolism*
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Up-Regulation
Substances
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Adaptor Proteins, Signal Transducing
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Chromones
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FADD protein, human
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FASLG protein, human
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Fas Ligand Protein
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Fas-Associated Death Domain Protein
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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CASP8 protein, human
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Caspase 8
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Caspases