The role of retinoblastoma protein in apoptosis

The retinoblastoma gene and its protein product (Rb) have been studied inte nsively for their role in development, oncogenesis, cell growth, differenti ation and cell cycle regulation. In addition, Rb appears to be a key factor in protecting cells from apoptosis. It is likely that Rb plays an essentia l role in cell survival by regulating the activity of multiple apoptotic me diators. Rb expression as a nuclear phosphoprotein is essential for normal cell cycle function. Clearly, any damage to the cell cycle or to DNA integr ity is a potent trigger of apoptosis and Rb involvement. The E2F transcript ion factor is a critical component in the Rb-dependent apoptotic pathway(s) , and can act either in concert or independently of the p53 tumour suppress or. Until recently, it was suggested that Rb, E2F and p53 modulate the apop totic threshold by acting upstream of certain death proteases involved in p rogrammed cell death. However, Rb activity can also be regulated downstream by the interleukin-converting enzyme-like (ICE-like) proteases, which abol ish Rb activity by cleavage of aspartate-enriched regions within its C-term inus. Finally, Bcl-2, which inhibits multiple-factorial-induced apoptosis, does so, in part, by modulating the phosphorylation state of Rb. Taken toge ther, Rb acts not only as a tumour suppressor protein which controls cell c ycle function, but also determines the final destiny of a cell through apop tosis.