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Genetic deletion of faim reveals its role in modulating c-FLIP expression during CD95-mediated apoptosis of lymphocytes and hepatocytes.

http://www.ncbi.nlm.nih.gov/pubmed/19300454

Fas-apoptosis inhibitory molecule (FAIM) is inducibly expressed in B lymphocytes and had been shown to antagonize Fas-mediated killing of B-cell lines in vitro. However, its mechanism and role in vivo are unknown. We have generated faim(-/-) mice and found these mutants to be viable. In contrast to fas(-/-) mice, faim(-/-) mice have normal B- and T-cell populations. However, faim(-/-) B cells and thymocytes show increased sensitivity to Fas-triggered apoptosis in vitro, and faim(-/-) mice suffer greater mortality and exhibit exacerbated liver damage in response to Fas (CD95) engagement in vivo. The lack of FAIM results in greater activation of caspase-8 and -3 in Fas-stimulated thymocytes. Detailed biochemical analyses further reveal the decreased expression of c-FLIP(L) and c-FLIP(R) in faim(-/-) thymocytes and increased association of caspase-8 with Fas in Fas-activated mutant cells. Decreased levels of c-FLIP(L) and c-FLIP(R) are also evident in faim(-/-) liver. Thus, FAIM plays a novel role in modulating Fas-mediated apoptosis and acts through influencing the expression of c-FLIP and regulating the physical binding of caspase-8 to Fas.

Pubmed ID: 19300454 RIS Download

Mesh terms: Animals | Anti-Inflammatory Agents | Antibodies, Monoclonal | Antigens, CD95 | Apoptosis | Apoptosis Regulatory Proteins | B-Lymphocytes | CASP8 and FADD-Like Apoptosis Regulating Protein | Caspase 3 | Caspase 8 | Dexamethasone | Fas Ligand Protein | Gene Deletion | Hepatocytes | Immunologic Factors | Liver | Mice | Mice, Knockout | T-Lymphocytes | Tumor Necrosis Factor-alpha

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Mouse Genome Informatics (Data, Gene Annotation)

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