title: Degradation of retinoblastoma protein in tumor necrosis factor- and CD95-induced cell death.
abstract: The product of the retinoblastoma susceptibility gene, RB, is a negative regulator of cell proliferation. Inactivation of RB does not interfere with embryonic growth or differentiation. However, Rb-deficient embryos show abnormal degeneration of neurons and lens fiber cells through apoptosis, suggesting that RB may protect against programmed cell death. Consistent with this notion, RB is found to be degraded in tumor necrosis factor (TNF)- and CD95-induced death. A consensus caspase cleavage site at the C terminus of RB is cleaved in vitro and in vivo by proteases related to CPP32 (caspase 3). Mutation of the consensus cleavage site generates a cleavage-resistant RB which is not degraded during cell death. Expression of this non-degradable RB is found to antagonize the cytotoxic effects of TNF in Rb-/- 3T3 cells, but this mutant RB cannot attenuate the rapid death induced by anti-CD95 in Jurkat/T cells. These results show that RB is a target of the caspase family of proteases during cell death and suggest that the failure to degrade RB can attenuate the death response toward some but not all death inducers.
authors.affiliation: Department of Biology and Center for Molecular Genetics, University of California at San Diego, La Jolla, California 92093-0347, USA.
authors.forename: X
authors.initials: X
authors.lastname: Tan
authors.forename: S J
authors.initials: SJ
authors.lastname: Martin
authors.forename: D R
authors.initials: DR
authors.lastname: Green
authors.forename: J Y
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002645:Chickens; D016384:Consensus Sequence; D003609:Dactinomycin / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016296:Mutagenesis; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014981:Xenopus; D019014:fas Receptor / Q000494:pharmacology*
chemical_list: D016160:Retinoblastoma Protein; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003609:Dactinomycin