The role of retinoblastoma protein in apoptosis.

The retinoblastoma gene and its protein product (Rb) have been studied intensively for their role in development, oncogenesis, cell growth, differentiation 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 essential role in cell survival by regulating the activity of multiple apoptotic mediators. Rb expression as a nuclear phosphoprotein is essential for normal cell cycle function. Clearly, any damage to the cell cycle or to DNA integrity is a potent trigger of apoptosis and Rb involvement. The E2F transcription factor is a critical component in the Rb-dependent apoptotic pathway(s), and can act either in concert or independently of the p53 tumour suppressor. Until recently, it was suggested that Rb, E2F and p53 modulate the apoptotic threshold by acting upstream of certain death proteases involved in programmed cell death. However, Rb activity can also be regulated downstream by the interleukin-converting enzyme-like (ICE-like) proteases, which abolish Rb activity by cleavage of aspartate-enriched regions within its C-terminus. Finally, Bcl-2, which inhibits multiple-factorial-induced apoptosis, does so, in part, by modulating the phosphorylation state of Rb. Taken together, Rb acts not only as a tumour suppressor protein which controls cell cycle function, but also determines the final destiny of a cell through apoptosis.