Disease relevance of Cflar

• These effects of c-FLIP collectively served to diminish the severity of CVB3-induced myocarditis [1].
• Augmentation of c-FLIP in TECs may enhance an endogenous mechanism by which TECs normally resist injury to caspase-8-mediated apoptosis and thus may be a useful and novel strategy to prevent tubular injury in transplant rejection and autoimmune nephritis [2].
• In vivo, c-FLIP expression results in defective superantigen-mediated elimination of T cells, the accumulation of activated B cells, the production of autoantibodies, and the development of autoimmune disease [3].
• Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression [4].

High impact information on Cflar

• Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development [5].
• We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development [5].
• Retrovirus-mediated expression of c-FLIP blocks Fas-induced apoptosis of activated lymphocytes but does not affect cell death resulting from cytokine withdrawal [3].
• Here, we show that both B and T cells downregulate c-FLIP upon activation in vitro [3].
• These results suggest that activation-dependent downregulation of c-FLIP renders mature lymphocytes sensitive to death receptor-mediated apoptosis and is required to maintain self-tolerance [3].

Biological context of Cflar

• Higher c-FLIP transgene expression was correlated with a more profound suppression of T-cell activation and a prominent disturbance in mature thymocyte development [6].
• The data suggest differential spatial and temporal regulation of cFLIP-alpha and cFLIP-delta expression that may influence the magnitude of cell death and further implicate programmed mechanisms of cell death after TBI [7].
• Other DED-containing proteins including cFLIP and DEDD can also regulate signal transduction events and transcription in addition to apoptosis [8].
• Specific downregulation of cFLIP expression using siRNA reversed the antiapoptotic effect of DEX by increasing caspase-8 activation [9].
• Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP [9].

Anatomical context of Cflar

• Keratins modulate c-Flip/extracellular signal-regulated kinase 1 and 2 antiapoptotic signaling in simple epithelial cells [10].
• This points to a new regulatory role of simple epithelium keratins in the c-Flip/ERK1/2 antiapoptotic signaling pathway [10].
• Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c-FLIP [11].
• Altogether these data suggest that c-Flip may control the survival rate of undifferentiated spermatogonia [12].
• The effects of c-FLIP on cytolytic function of CD8(+) T cells have not been examined previously [1].

Associations of Cflar with chemical compounds

• Expression of c-FLIP significantly increased the resistance towards gemcitabine [13].
• The antiapoptotic effect of bortezomib was likely mediated by an increase in hepatic cellular FLICE inhibitory protein (c-FLIP) levels, a potent antiapoptotic protein [14].
• Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC [15].
• We found that c-FLIP promoter contained multiple functional androgen response elements [16].
• The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-beta but were reversed by the proteasome inhibitor lactacystin [17].

Regulatory relationships of Cflar

• As a key inhibitor of Fas-mediated apoptosis, we found expression of the cellular FLICE-inhibitory protein (c-FLIP) to be induced by TGF-beta in resting as well as in activated microglia [18].
• Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-kappaB activation and life/death decisions in lymphocytes and DCs [19].
• In this regard, caspase-12 seems to be the cFLIP counterpart for regulating the inflammatory branch of the caspase cascade [20].

Other interactions of Cflar

• In conclusion, both c-FLIP proteins prevent caspase-8 activation at different levels of procaspase-8 processing at the DISC [21].
• CONCLUSION: This is the first report of c-FLIP regulation by IL-2 in renal TECs [2].
• Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor-induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process [22].
• Their survival was associated with expression of antiapoptotic cellular FLICE-inhibitory protein (c-FLIP), Bcl-X(L), and Bcl-2 [23].
• Retroviral transduction of RelA(-/-) B cells with either cFLIP or Bcl-2 significantly reduced TNF-alpha killing [24].

Analytical, diagnostic and therapeutic context of Cflar

• Animal models have indicated that c-FLIP plays an important role in T cell proliferation and heart development [25].
• Porcine (Sus scrofa) cellular FLICE-like inhibitory protein (cFLIP): molecular cloning and comparison with the human and murine cFLIP [26].

References