c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity
Résumé
Akt is a serine threonine kinase that plays 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 c-DNA as bait and a human c-DNA heart library as prey. Among 200 clones obtained, two of them were identified as coding for the c-FLIPL protein. c-FLIPL is an endogenous inhibitor of death receptor-induced apoptosis through the caspase 8 pathway. By co-immunoprecipitation experiments of either transfected or endogenous proteins, we confirmed the interaction between Akt and c-FLIPL. Further, we found that c-FLIPL overexpression interferes with Gsk3-β phosphorylation levels. Moreover, through its effects on Gsk3β, c-FLIPL overexpression in cancer cells induced resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This effect was mediated by the regulation of p27Kip1 and caspase 3 expression. These results indicate the existence of a novel mechanism of resistance to TRAIL in cancer cells, and unexpected functions of c-FLIPL.
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