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.