DEGRADATION OF RETINOBLASTOMA PROTEIN IN TUMOR NECROSIS FACTOR-INDUCED AND CD95-INDUCED CELL-DEATH

The product of the retinoblastoma susceptibility gene, RB, is a negati ve regulator of cell proliferation. Inactivation of RE does not interf ere with embryonic growth or differentiation. However, Rb-deficient em bryos show abnormal degeneration of neurons and lens fiber cells throu gh apoptosis, suggesting that RE may protect against programmed cell d eath. Consistent with this notion, RE is found to be degraded in tumor necrosis factor (TNF)- and CD95-induced death, A consensus caspase cl eavage site at the C terminus of RE is cleaved in vitro and in vivo by proteases related to CPP32 (caspase 3). Mutation of the consensus cle avage site generates a cleavage-resistant RE which is not degraded dur ing cell death. Expression of this non-degradable RE is found to antag onize the cytotoxic effects of TNF in Rb-/- 3TS cells, but this mutant RE cannot attenuate the rapid death induced by anti-CD95 in Jurkat/T cells. These results show that RE is a target of the caspase family of proteases during cell death and suggest that the failure to degrade R E can attenuate the death response toward some but not all death induc ers.