Signal-dependent protection from apoptosis in mice expressing caspase-resistant Rb.
The retinoblastoma tumour suppressor protein RB is cleaved by caspases during apoptosis. Here we have mutated the caspase cleavage site in the carboxy terminus of the murine Rb protein in the mouse germ line to create the Rb-MI allele. After endotoxic shock, expression of Rb-MI inhibits apoptosis in the intestines, but not in the spleen, and promotes the survival of male mice. Fibroblasts expressing Rb-MI protein are protected from apoptosis induced by the tumour-necrosis factor-alpha type I receptor (TNFRI) but remain sensitive to cell death induced by DNA damage. Correspondingly, the release of cytochrome c and the activation of caspase-3 induced by TNFRI, but not by DNA damage, are defective in cells expressing Rb-MI. Our results highlight the importance of Rb cleavage in TNFRI-induced apoptosis.
D016475:3T3 Cells; D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012160:Retina / Q000254:growth & development / Q000378:metabolism / Q000528:radiation effects; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014118:Toxins, Biological; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D015703:Antigens, CD; D003574:Cytochrome c Group; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D016160:Retinoblastoma Protein; D014118:Toxins, Biological; D014409:Tumor Necrosis Factor-alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases