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Inhibition of death receptor signals by cellular FLIP
1Institute of Biochemistry, Lausanne branch, University of Lausanne, Switzerland.
Abstract:
The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis. However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals, indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIPs, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis, whereas the long form, FLIP(L), contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPs and FLIP(L) interact with the adaptor protein FADD and the protease FLICE, and potently inhibit apoptosis induced by all known human death receptors. FLIP(L) is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIP(L) protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis.
Insights
Researchers identified FLIP (FLICE-inhibitory protein), an apoptosis inhibitor found in muscle and lymphoid tissues. FLIP, in its short (FLIPs) and long (FLIP(L)) forms, inhibits apoptosis signals from all known human death receptors.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Fas receptor, a member of the tumor necrosis factor receptor family, triggers apoptosis.
- Fas surface expression does not guarantee cell susceptibility to Fas ligand-induced death signals, implying the existence of apoptosis pathway inhibitors.
Purpose of the Study:
- To characterize a novel inhibitor of apoptosis, FLIP (FLICE-inhibitory protein).
- To investigate the role of FLIP in apoptosis regulation and its potential involvement in disease.
Main Methods:
- Protein characterization of FLIP (short form FLIPs and long form FLIP(L)).
- Analysis of FLIP interactions with adaptor protein FADD and protease FLICE.
- Assessment of FLIP's inhibitory effects on apoptosis induced by human death receptors.
- Examination of FLIP(L) expression during T-cell activation and in melanoma.
Main Results:
- FLIP is predominantly expressed in muscle and lymphoid tissues.
- FLIPs contains two death effector domains; FLIP(L) contains an additional caspase-like domain with a substituted active-site cysteine.
- Both FLIPs and FLIP(L) interact with FADD and FLICE, potently inhibiting apoptosis from all known human death receptors.
- FLIP(L) expression is transient during early T-cell activation and is highly expressed in melanoma cell lines and tumors.
Conclusions:
- FLIP (FLICE-inhibitory protein) is a potent inhibitor of apoptosis.
- FLIP(L) expression dynamics suggest its role in regulating T-cell apoptosis susceptibility.
- Elevated FLIP(L) in melanoma indicates its potential implication in cancer pathogenesis.
- FLIP may play a significant role in maintaining tissue homeostasis through apoptosis regulation.