15665818

pubmed:Citation

3

In T lymphocytes, the role of Akt in regulating Fas/Fas ligand (FasL)-mediated apoptotic signaling and death is not clearly understood. In this study, we observed that inhibition of Akt causes enhanced expression of FasL mRNA and protein and increased death-inducing signaling complex (DISC) formation with Fas-associated death domain (FADD) and procaspase-8 recruitment. Also, caspase-8 was activated at the DISC with accompanying decrease in c-FLIPs expression. FasL neutralizing antibody significantly decreased apoptotic death in the Akt-inhibited T cells. Additionally, Akt inhibition-induced Fas signaling was observed to link to the mitochondrial pathway via Bid cleavage. Further, inhibition of caspase-8 activity effectively blocked the loss of mitochondrial membrane potential and DNA fragmentation, suggesting that DISC formation and subsequent caspase-8 activation are critical initiating events in Akt inhibition-induced apoptotic death in T lymphocytes. These data demonstrate yet another important survival function governed by Akt kinase in T lymphocytes, which involves the regulation of FasL expression and consequent apoptotic signaling.

eng

IM

MEDLINE

1350-9047

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NLM

233-42

pubmed-meshheading:15665818-Adaptor Proteins, Signal Transducing, pubmed-meshheading:15665818-Apoptosis, pubmed-meshheading:15665818-BH3 Interacting Domain Death Agonist Protein, pubmed-meshheading:15665818-CASP8 and FADD-Like Apoptosis Regulating Protein, pubmed-meshheading:15665818-Carrier Proteins, pubmed-meshheading:15665818-Caspase 8, pubmed-meshheading:15665818-Caspases, pubmed-meshheading:15665818-Chromones, pubmed-meshheading:15665818-Down-Regulation, pubmed-meshheading:15665818-Fas Ligand Protein, pubmed-meshheading:15665818-Fas-Associated Death Domain Protein, pubmed-meshheading:15665818-Humans, pubmed-meshheading:15665818-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:15665818-Jurkat Cells, pubmed-meshheading:15665818-Membrane Glycoproteins, pubmed-meshheading:15665818-Membrane Potentials, pubmed-meshheading:15665818-Mitochondria, pubmed-meshheading:15665818-Morpholines, pubmed-meshheading:15665818-Phosphatidylinositol 3-Kinases, pubmed-meshheading:15665818-Protein-Serine-Threonine Kinases, pubmed-meshheading:15665818-Proto-Oncogene Proteins, pubmed-meshheading:15665818-Proto-Oncogene Proteins c-akt, pubmed-meshheading:15665818-Signal Transduction, pubmed-meshheading:15665818-T-Lymphocytes, pubmed-meshheading:15665818-Up-Regulation

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural