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

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

Authors

  • Huo J
  • Xu S
  • Guo K
  • Zeng Q
  • Lam KP

Journal

Cell death and differentiation

Publication Data

July 16, 2009

Associated Grants

None

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