c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity

• Published in: Cell death and differentiation Vol. 17; no. 12; pp. 1908 - 1916
• 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: London Nature Publishing Group UK 01.12.2010; Nature Publishing Group
• Subjects: 631/45/612/1234; 631/80/82/23; 631/80/86; Apoptosis; Biochemistry; Biomedical and Life Sciences; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; CASP8 and FADD-Like Apoptosis Regulating Protein - physiology; Caspase 3 - metabolism; Caspase 8 - metabolism; Cell Biology; Cell Cycle Analysis; Cell Line; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - physiology; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; Life Sciences; Lithium Chloride - pharmacology; original-paper; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Stem Cells; TNF-Related Apoptosis-Inducing Ligand - pharmacology; apoptosis; AKT; Bcl-2 family; TRAIL
• 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- β phosphorylation levels. Moreover, through its effects on Gsk3 β , 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 .