Disease relevance of CFLAR

• Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death [1].
• In vivo, a Usurpin deficit was found in cardiac infarcts where TUNEL-positive myocytes and active caspase-3 expression were prominent following ischemia/reperfusion injury [2].
• Our major conclusions are: (a) The death receptor pathway is differently inactivated at multiple levels in lung cancer cell lines; and (b) MYC amplification in SCLC is associated with inactivation of most components of the DISC complex, with resistance to TRAIL and with expression of c-FLIP [3].
• Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy [4].
• Downregulation of c-FLIP sensitizes DU145 prostate cancer cells to Fas-mediated apoptosis [5].
• These results indicate that c-FLIP inhibits spontaneous death ligand-independent, death receptor-mediated apoptosis in colorectal cancer cells and that targeting c-FLIP may have therapeutic potential for the treatment of colorectal cancer [6].

Psychiatry related information on CFLAR

• BACKGROUND: Flame injury confers significant physical and psychologic stress on burn patients [7].
• Commentary on McSherry W, Cash K & Ross L (2004) Meaning of spirituality: implications for nursing practice. Journal of Clinical Nursing 13, 934-941 [8].
• Body image, as measured by the Appearance Evaluation and Body Areas Satisfaction scales of the Multidimensional Body-Self Relations Questionnaire (T.F. Cash, 1994b), was assessed in 59 obese women before, during, and after 48 weeks of weight loss treatment [9].
• Mental health forum. 1. Cash on delivery [10].
• Given evidence that questionnaire assessment of panic results in substantial false positives (Brown & Cash, 1989, Journal of Anxiety Disorders, 3, 139-148), it was hypothesized that familial aggregation differences could be largely attributable to this phenomenon as well [11].

High impact information on CFLAR

• Casper is a FADD- and caspase-related inducer of apoptosis [12].
• A C-terminal deletion mutant of Casper inhibits TNF- and Fas-induced cell death, suggesting that Casper is involved in these apoptotic pathways [12].
• When overexpressed in mammalian cells, Casper potently induces apoptosis [12].
• Despite expression of other NF-kappaB-dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis [13].
• Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane [13].

Chemical compound and disease context of CFLAR

• Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression [14].
• Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein [15].
• These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells [16].
• We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan) [17].
• Reconstitution of TRAF-2-/- EF with c-FLIP is sufficient for resistance to TNF toxicity [18].

Biological context of CFLAR

• Thus, CLARP represents a regulator of the upstream caspase-8, which may play a role in apoptosis during tissue development and homeostasis [19].
• Down-regulation of cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) through the use of specific small inhibitory RNAs (siRNAs) leads to reduced viability of the L428 and L591 HL-derived cell lines [1].
• MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death [20].
• Treatment of these cells with both c-FLIP- and FasL-specific siRNAs in combination restored cell viability to near control levels [1].
• We have isolated a gene, termed MRIT, that possesses overall sequence homology to FLICE (MACH), a large prodomain caspase that links the aggregated complex of the death domain receptors of the tumor necrosis factor receptor family to downstream caspases [20].

Anatomical context of CFLAR

• Here we confirm that both HL-derived cell lines and the HRS cells of primary HL tissues express Fas ligand (FasL) along with the inhibitory c-FLIP protein [1].
• Usurpin thus appears to be an endogenous modulator of apoptosis sensitivity in mammalian cells, including the susceptibility of cardiac myocytes to apoptotic death following ischemia/ reperfusion injury [2].
• Phosphatidylinositide 3-kinase priming couples c-FLIP to T cell activation [21].
• Similarly there is strong c-FLIP immunoreactivity in SMCs from nonatherosclerotic diffuse intimal thickening and in the overlying endothelial cells [22].
• A direct comparison revealed that distinct signal pathways were regulated by c-FLIP in Jurkat cells and DO11.10 cells [21].

Associations of CFLAR with chemical compounds

• However, both caspase 8 and caspase 10 recruitment and processing within the TRAIL death-inducing signaling complex (DISC) were greater in GCDCA-treated cells whereas recruitment of cFLIP long and short was reduced [23].
• Death receptors trigger apoptosis by activating the apical cysteine proteases caspase-8 and -10 within a death-inducing signaling complex (DISC). c-FLIP (cellular FLICE inhibitory protein) is an enzymatically inactive relative of caspase-8 and -10 that binds to the DISC [24].
• Cross-resistance to death ligand-induced apoptosis in cisplatin-selected HeLa cells associated with overexpression of DDB2 and subsequent induction of cFLIP [25].
• Cell death was only observed in the presence of cycloheximide or after a pulse through CD3 or CD59, correlating with a net reduction in cellular Fas-associated death domain-like IL-1beta-converting enzyme-inhibitory protein long (c-FLIPL) and c-FLIPS expression [26].
• In contrast, in response to doxorubicin, levels of c-FLIP, particularly FLIP(S), decreased in all cell lines tested [14].

Physical interactions of CFLAR

• In addition, MRIT simultaneously and independently interacts with BclXL and FLICE in mammalian cells [20].
• Moreover, we show that a cellular membrane permeable version of the peptide corresponding to the DR5 binding domain of c-FLIP induces apoptosis in mammalian cells [27].
• CASPER is an increment rule-based approach which uses chemical shifts of the free reducing monosaccharides which are altered according to attached residues of an oligo- or polysaccharide sequence [28].

Regulatory relationships of CFLAR

• In stably transfected BJAB cells, c-FLIP blocks caspase-8 activation at the DISC and thereby inhibits CD95-mediated apoptosis [29].
• Accordingly, the elimination of cFLIP by antisense oligonucleotides suppresses DDB2 protection [25].
• After JO2 exposure, CFLAR (L) protein levels were enhanced only at the nonpermissive TRP53 temperature (37 degrees C) while real-time PCR results indicated an absence of Cflar (L) mRNA changes in GC-2 cells regardless of the temperature [30].
• In this study, we demonstrated that TNF-alpha-induced cell proliferation is achieved through the c-FLIP [31].
• ASC-mediated NF-kappaB activation leading to interleukin-8 production requires caspase-8 and is inhibited by CLARP [32].

Other interactions of CFLAR

• However, unlike FLICE, the C-terminal domain of MRIT lacks the caspase catalytic consensus sequence QAC(R/Q)G [20].
• CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis [19].
• The role of c-FLIP in modulation of CD95-induced apoptosis [29].
• Fas-associated protein with death domain (FADD)-independent recruitment of c-FLIPL to death receptor 5 [27].
• Interestingly, FLAME-1 is recruited to the Fas receptor complex and can abrogate Fas/TNFR-induced apoptosis upon expression in FasL/tumor necrosis factor-sensitive MCF-7 cells, possibly by acting as a dominant-negative inhibitor [33].

Analytical, diagnostic and therapeutic context of CFLAR

• By in situ hybridization and immunohistochemistry, we demonstrate that c-FLIP is expressed in endothelial cells, macrophages, and smooth muscle cells (SMCs) both in human coronary arteries and in cultured cells [22].
• After balloon angioplasty, c-FLIP protein is rapidly down-regulated in medial SMCs for 2 weeks and regains expression by 4 weeks [22].
• MATERIALS AND METHODS: To selectively interfere with expression of cFLIP short double-stranded RNA oligonucleotides (small interfering RNAs [siRNAs]) were introduced in the human cell lines SV80 and KB by electroporation [34].
• These data suggested that intracellular remodeling with overexpression of pig c-FLIP in xenograft cells may decrease the innate cellular responses against xenografts, facilitating long-term xenograft survival [35].
• METHODS: Biopsy specimens and LPLs were taken from CD and ulcerative colitis (UC) patients and normal controls and analyzed for Flip by Western blotting [36].

References