Nuclear localization of c-FLIP-L and its regulation of AP-1 activity.
Cellular FLICE-like inhibitory protein (c-FLIP-L), similar in structure to caspase-8, is capable of blocking Fas- or other death receptors (DR)-mediated apoptosis through association with FADD in the DISC. Recent studies have implicated the function of c-FLIP-L in T-cell proliferation, but the exact mechanism underlying this process remains to be elucidated. In this report, we showed for the first time that c-FLIP-L was present in both the cytoplasm and nucleus of cells, but was more abundantly distributed in the nucleus. The putative NLS signal locates within the p12 region of caspase-like domain. Furthermore, c-FLIP's export to cytoplasm membrane was dependent on apoptotic stimulation, while it rapidly translocated to the nucleus in response to proliferative stimuli. To gain insights into the possible function of c-FLIP-L in the nucleus, we found c-FLIP-L could activate the AP-1 transcriptional activity independent of MAPK activation. In sum, our findings describe a novel function of c-FLIP-L involved in AP-1 activation and cell proliferation.
Jiangsu Center of Hepatobiliary Diseases and the State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Gulou Hospital, School of Life Sciences, Nanjing University, Nanjing, China.
Jing
J
Zhang
Yunzi
Y
Chen
Qilai
Q
Huang
Wei
W
Cheng
Yuanxi
Y
Kang
Luan
L
Shu
Wu
W
Yin
Zi-Chun
ZC
Hua
D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D019913:Nuclear Localization Signals / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; D008934:Mitogens; D019913:Nuclear Localization Signals; D020033:Protein Isoforms; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases