C-FLIP Modulated Wnt/β-Catenin Activation via Association with TIP49 Protein.

Cellular FLICE-like inhibitory protein (c-FLIP) is a key inhibitory protein in the extrinsic apoptotic pathway. Recent studies showed that c-FLIP could translocate into the nucleus and might be involved in the Wnt signaling pathway. The nuclear function of c-FLIP was still unclear. Here we found a novel c-FLIP-associated protein TIP49, which is a nuclear protein identified as a cofactor in the transcriptional regulation of β-catenin. They had co-localization in the nucleus and the DED domain of c-FLIP was required for the association with TIP49. By performing ChIP experiments, C-FLIP was detected in the ITF-2 locus and facilitated TIP49 accumulation in the formation of complexes at the T-cell-specific transcription factor site of human ITF-2 promoter. When TIP49 knockdown, c-FLIP-driven Wnt activation, and cell proliferation were inhibited, suggesting that a role of nuclear c-FLIP involved in modulation of the Wnt pathway was in a TIP49-dependent manner. Elevated expression of c-FLIP and TIP49 that coincided in human lung cancers were analyzed using the Oncomine database. Their high expressions were reconfirmed in six lung cancer cell lines and correlated with cell growth. The association of c-FLIP and TIP49 provided an additional mechanism involved in c-FLIP-mediated functions, including Wnt activation.