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.