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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Sci+Signal 2012 ; 5 (255): ra93 Nephropedia Template TP
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c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis #MMPMID23250397
Piao X; Komazawa-Sakon S; Nishina T; Koike M; Piao JH; Ehlken H; Kurihara H; Hara M; Van Rooijen N; Schütz G; Ohmuraya M; Uchiyama Y; Yagita H; Okumura K; He YW; Nakano H
Sci Signal 2012[Dec]; 5 (255): ra93 PMID23250397show ga
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 ?B (NF-?B) 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-?B?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?? (TNF-?) 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-?, 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-?, FasL, and TRAIL.