Cell Death Differ 2002,
PMID: 12404126
Ruefli, A A; Tainton, K M; Darcy, P K; Smyth, M J; Johnstone, R W
Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein, P-gp, can specifically inhibit Fas-induced caspase-3 activation and apoptosis. Importantly, inhibition of both caspase-3 activation and cell death could be reversed by pharmacological and antibody inhibitors of P-gp function. However, the molecular mechanisms underpinning P-gp-mediated resistance to Fas-induced cell death and caspase activation remained unknown. We therefore sought to identify the point(s) within the death receptor pathway at which P-gp exerted its inhibitory effect and to determine whether the ATPase activity of P-gp was required. Structure-function analysis determined that ATP hydrolysis was necessary for P-gp to confer resistance to Fas-induced caspase activation and cell death. Importantly, although both FADD and caspase-8 were recruited to the Death Inducing Signal Complex (DISC) in wild-type P-gp expressing cells following Fas ligation, subsequent activation of caspase-8 at the DISC was inhibited. The ability of P-gp to inhibit caspase-8 activation was also ATP dependent. These studies demonstrate that P-gp inhibits Fas-induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis.
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Text Mining Data
caspase-8 ⊣ P-glycoprotein: "
P-glycoprotein inhibits
caspase-8 activation but not formation of the death inducing signal complex ( disc ) following Fas ligation
"
caspase-3 ⊣ P-glycoprotein: "
Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein , P-gp, can specifically inhibit Fas induced caspase-3 activation and apoptosis
"
caspase-3 → Fas: "
Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein, P-gp, can specifically inhibit Fas induced caspase-3 activation and apoptosis
"
caspase → Fas: "
However, the molecular mechanisms underpinning P-gp mediated resistance to Fas induced cell death and caspase activation remained unknown
"
caspase → Fas: "
Structure-function analysis determined that ATP hydrolysis was necessary for P-gp to confer resistance to Fas induced caspase activation and cell death
"
caspase-8 ⊣ P-gp: "
The ability of P-gp to inhibit caspase-8 activation was also ATP dependent
"
caspase-8 ⊣ P-gp: "
These studies demonstrate that P-gp inhibits Fas induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis
"
caspase-8 → Fas: "
These studies demonstrate that P-gp inhibits Fas induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis
"
Manually curated Databases
No curated data.