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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-FLIPL protein. c-FLIPL 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-FLIPL. Furthermore, we observed 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 new mechanism of resistance to TRAIL in cancer cells, and unexpected functions of c-FLIPL. [ABSTRACT FROM AUTHOR]

Death receptors, belonging to the TNF receptor superfamily, induce apoptosis through two different pathways, one involving the effector caspases directly (type I cells or mitochondria-independent death), the other one amplifying the death signal through the mitochondrial pathway (type II cells or mitochondria-dependent death). MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate the stability or translational efficiency of targeted messenger RNAs. MiRNAs are involved in many cellular processes that are altered in cancer, such as differentiation, proliferation and apoptosis. In this review we will discuss recent findings implicating miRNAs as regulators of death receptors and pro- and antiapoptotic genes involved in programmed cell death pathways. [ABSTRACT FROM AUTHOR]