Long form of cellular FLICE-inhibitory protein interacts with Daxx and prevents Fas-induced JNK activation.
Since Fas-induced apoptosis is major pathway to eliminate unwanted or uncontrolled cells, many types of human cancer cells develop tactful mechanisms to get resistance against the apoptosis. One of the resistant mechanisms in human cancer is overexpression of FLICE-inhibitory protein (c-FLIP), human homolog of viral protein v-FLIP. c-FLIP has multiple splice variants at transcriptional level or two isoforms at protein level, a long (c-FLIP(L)) and a short form of c-FLIP (c-FLIP(S)). However, functional differences between these variants are not fully understood. In this study, we show that c-FLIP(L) but not c-FLIP(S) physically binds to Daxx through interaction between C-terminal domain of c-FLIP(L) and Fas-binding domain of Daxx, an alternative Fas signaling adaptor. Fas-induced cell death and JNK activation are sensitive to Fas stimulation in cell lines carrying undetectable level of c-FLIP(L). To support this, overexpression of c-FLIP(L) but not of c-FLIP(S) renders the cells resistant to Fas-induced cell death and to JNK activation. In signaling context, the interaction of c-FLIP(L) with Daxx is likely to inhibit JNK activation by preventing the normal interaction of Daxx and Fas, which is known to lead to apoptosis via JNK activation. This study implies that through this new mechanism, c-FLIP(L), acting at both FADD- and Daxx-mediated signaling pathways, may be involved in complete inhibition of Fas-induced cell death and may provide an answer to why c-FLIP(L) is more abundant and effective than c-FLIP(S).
Kim
Young-Youl
YY
National Genome Research Institute, National Institute of Health in Korea (KNIH) Nokbun-Dong 5, Eunpyung-Gu, 122-701, Seoul, Republic of Korea
Park
Bum-Joon
BJ
Seo
Gill-Ju
GJ
Lim
Joong-Yeon
JY
Lee
Sang-Min
SM
Kimm
Kyu-Chan
KC
Park
Chan
C
Kim
Joon
J
Park
Sang Ick
SI
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D019014:fas Receptor / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases