Alternative splicing variants of c-FLIP transduce the differential signal through the Raf or TRAF2 in TNF-induced cell proliferation.
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.
Park
S J
SJ
Department of Cancer Research, National Institute of Health in Korea (KNIH), Seoul, 122-701, Korea.
Kim
Y Y
YY
Ju
J W
JW
Han
B G
BG
Park
S I
SI
Park
B J
BJ
D017398:Alternative Splicing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C506386:CFLAR protein, human