c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3[beta] activity

• Published in: Cell death and differentiation Vol. 17; no. 12; p. 1908
• Main Authors: Quintavalle, C, Incoronato, M, Puca, L, Acunzo, M, Zanca, C, Romano, G, Garofalo, M, Iaboni, M, Croce, C M, Condorelli, G
• Format: Journal Article
• Language: English
• Published: Rome Nature Publishing Group 01.12.2010
• Subjects: Apoptosis; Cancer; Cell cycle; Cell death; Cloning; Kinases; Ligands; Phosphorylation; Proteins; Transcription factors; Tumor necrosis factor-TNF; Italy
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.65

Akt is a serine-threonine kinase that has an important role in transducing survival signals. Akt also regulates a number of proteins involved in the apoptotic process. To find new Akt interactors, we performed a two-hybrid screening in yeast using full-length Akt cDNA as bait and a human cDNA heart library as prey. Among 200 clones obtained, two of them were identified as coding for the c-FLIP(L) protein. c-FLIP(L) is an endogenous inhibitor of death receptor-induced apoptosis through the caspase-8 pathway. Using co-immunoprecipitation experiments of either transfected or endogenous proteins, we confirmed the interaction between Akt and c-FLIP(L). Furthermore, we observed that c-FLIP(L) overexpression interferes with Gsk3-[beta] phosphorylation levels. Moreover, through its effects on Gsk3[beta], c-FLIP(L) overexpression in cancer cells induced resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This effect was mediated by the regulation of p27(Kip1) and caspase-3 expression. These results indicate the existence of a new mechanism of resistance to TRAIL in cancer cells, and unexpected functions of c-FLIP(L).