Abstract
The caspase-8 homologue FLICE-inhibitory protein (FLIP) functions as a caspase-8 dominant negative, blocking apoptosis induced by the oligomerization of the adapter protein FADD/MORT-1. FLIP expression correlates with resistance to apoptosis induced by various members of the tumor necrosis factor family such as TRAIL. Furthermore, forced expression of FLIP renders cells resistant to Fas-mediated apoptosis. Although FLIP expression is regulated primarily by MEK1 activity in activated T cells, the oncogenic signaling pathways that regulate FLIP expression in tumor cells are largely unknown. In this report, we examined the roles of the MAP kinase and phosphatidylinositol (PI) 3-kinase signaling pathways in the regulation of FLIP expression in tumor cells. We observed that the MEK1 inhibitor PD98059 reduced FLIP levels in only 2 of 11 tumor cell lines tested. In contrast, disruption of the PI 3-kinase pathway with the specific inhibitor LY294002 reduced Akt (protein kinase B) phosphorylation and the levels of FLIP protein and mRNA in all cell lines evaluated. The introduction of a dominant negative Akt adenoviral construct also consistently reduced FLIP expression as well as the phosphorylation of the Akt target glycogen synthase kinase-3. In addition, infection of the same cell lines with a constitutively active Akt adenovirus increased FLIP expression and the phosphorylation of GSK-3. These data add FLIP to the growing list of apoptosis inhibitors in which expression or function is regulated by the PI 3-kinase-Akt pathway.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis
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Apoptosis Regulatory Proteins
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Blotting, Western
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Carrier Proteins / metabolism*
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Cell Line
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Genes, Dominant
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Humans
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Intracellular Signaling Peptides and Proteins*
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MAP Kinase Kinase 1
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Membrane Glycoproteins / metabolism
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / metabolism
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Signal Transduction
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T-Lymphocytes / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Apoptosis Regulatory Proteins
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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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Enzyme Inhibitors
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Flavonoids
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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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RNA, Messenger
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Glycogen Synthase Kinases
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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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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one