Abstract
In human cancer, despite apoptotic activity, death-ligand promotes the cell cycle progression under certain conditions. In this study, we demonstrated that TNF-alpha-induced cell proliferation is achieved through the c-FLIP. In addition, alternative splicing variants (c-FLIP(L) and c-FLIP(S)) contribute the TNF-alpha-induced cell cycle promotion through distinct pathways. The long form of c-FLIP (c-FLIP(L)) activates the Raf, which enhance the activity of Erk and PI3K, whereas short form (c-FLIPS) are activated by c-jun-N-terminal Kinase (JNK) through the TNF receptor-associated factor (TRAF) 2. Since, however, recruitment of c-FLIP(L) into FADD is later than that of c-FLIP(S), the activation of PI3K and Erk show the late response to activation of JNK. We also show that each c-FLIP variant is regulated by a distinct molecular mechanism at the transcriptional level; c-FLIP(L) is induced by Erk, whereas c-FLIP(S), through the JNK activation, is like an autocrine regulatory loop. Therefore, the induction of c-FLIP(L) in response to TNF-alpha is achieved in a more delayed manner than that of c-FLIP(S). Our present study also implies that other alternative splicing variants perform differential roles in spite of the same pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Cell Division / drug effects
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Cell Division / physiology
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Cell Line
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Enzyme Activation / drug effects
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Genetic Variation
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Humans
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Intracellular Signaling Peptides and Proteins*
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Serine-Threonine Kinases*
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Proteins / metabolism*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf / metabolism*
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Signal Transduction
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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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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Intracellular Signaling Peptides and Proteins
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Proteins
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Proto-Oncogene Proteins
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases