| First Author | Piao X | Year | 2012 |
| Journal | Sci Signal | Volume | 5 |
| Issue | 255 | Pages | ra93 |
| PubMed ID | 23250397 | Mgi Jnum | J:259529 |
| Mgi Id | MGI:6142020 | Doi | 10.1126/scisignal.2003558 |
| Citation | Piao X, et al. (2012) c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. Sci Signal 5(255):ra93 |
| abstractText | As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8. The transcription factor nuclear factor kappaB (NF-kappaB) plays a pivotal role in maintaining the homeostasis of the intestine and the liver by preventing death receptor-induced apoptosis, and c-FLIP plays a role in the NF-kappaB-dependent protection of cells from death receptor signaling. Because c-Flip-deficient mice die in utero, we generated conditional c-Flip-deficient mice to investigate the contribution of c-FLIP to homeostasis of the intestine and the liver at developmental and postnatal stages. Intestinal epithelial cell (IEC)- or hepatocyte-specific deletion of c-Flip resulted in perinatal lethality as a result of the enhanced apoptosis and programmed necrosis of the IECs and the hepatocytes. Deficiency in the gene encoding tumor necrosis factor-alpha (TNF-alpha) receptor 1 (Tnfr1) partially rescued perinatal lethality and the development of colitis in IEC-specific c-Flip-deficient mice but did not rescue perinatal lethality in hepatocyte-specific c-Flip-deficient mice. Moreover, adult mice with interferon (IFN)-inducible deficiency in c-Flip died from hepatitis soon after depletion of c-FLIP. Pretreatment of IFN-inducible c-Flip-deficient mice with a mixture of neutralizing antibodies against TNF-alpha, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) prevented hepatitis. Together, these results suggest that c-FLIP controls the homeostasis of IECs and hepatocytes by preventing cell death induced by TNF-alpha, FasL, and TRAIL. |
