FLIP: a flop for execution signals.
Resistance to apoptosis is one of the established hallmarks of cancer cells. This is a function of an imbalance between the proteins that facilitate death execution and those that inhibit apoptosis or promote cell proliferation. The anti-apoptotic protein, FLICE inhibitory protein (FLIP), first identified as a viral protein, is over-expressed in a variety of human pathologies. Initial observations linked FLIP expression to inhibition of death receptor induced apoptosis, due to its structural homology to the cysteine protease, caspase-8. FLIP impedes full processing of pro-caspase-8 to its active form and its release to the cytosol, and by doing so blocks apoptotic signaling downstream of the membrane death initiating signaling complex (DISC). Recent observations have highlighted the complex regulation of this protein and its cross talk with diverse signaling networks and metabolic processes. As FLIP expression is directly associated with chemotherapy resistance, a better understanding of its genomic organization, gene transcription, as well as post-transcriptional regulation could yield novel targets with potential therapeutic implications against drug refractory cancers. In this short review, we provide a brief overview of the structural and functional biology of this somewhat complex protein with direct relevance to carcinogenesis.
Apoptosis, ROS and Cancer Biology Program, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Kothandharaman
K
Subramaniam
Jayshree L
JL
Hirpara
Lisa
L
Tucker-Kellogg
Greg
G
Tucker-Kellogg
Shazib
S
Pervaiz
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D015894:Genome, Human; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D015398:Signal Transduction
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D020033:Protein Isoforms; D053181:Caspase 8