The activity of caspase-family proteases is central to cell-death execution, although there is evidence for alternative caspase-independent pathways. Many proteins are cleaved by caspases during apoptosis, but whether a particular cut is actually required for cell death, or whether it is just a bystander event, is not always known. An elegant study by Jean Wang and colleagues published in Nature Cell Biology now shows that cleavage of retinoblastoma protein (Rb) is required for apoptosis of certain tissues in response to specific death stimuli.

The cell-cycle regulator Rb is cleaved by caspases during apoptosis. The cleavage products are unstable and further degraded, resulting in the loss of Rb protein. Rb-knockout mice show ectopic apoptosis, and fibroblasts derived from Rb-deficient mice are hypersensitive to apoptosis induced by DNA damage and by tumour-necrosis factor (TNF)-α. But, is cell death caused by the inability of Rb-deficient cells to undergo cell-cycle arrest, or does Rb have a specific function in the inhibition of apoptosis, independent of its regulation of cell-cycle progression?

To address this issue, Wang and colleagues generated mice (Rb-MI) that contain a germline mutation in the caspase cleavage site in the Rb-1 gene. Consistent with previous results in transfected fibroblasts, they found that expression of a caspase-resistant mutant of Rb results in protection from TNF-α-induced cell death. More surprisingly, and in contrast to Rb-deficient mice, Rb-MI mice were as sensitive to radiation-induced apoptosis as wild-type mice.

In addition to the stimulus-specific effect of the Rb mutation, the authors also noticed cell-type-specific effects. Wild-type mice treated with bacterial lipopolysaccharide (LPS) undergo endotoxic shock and show massive cell death in the intestine and in the spleen. By contrast, the Rb-MI mutation protects intestinal cells, but not splenocytes, from LPS-induced cell death, and allows male, but not female, mice to survive.

So, this study indicates that cleavage and degradation of Rb is required for particular cell-death signalling pathways. The findings also raise questions regarding the mechanism of Rb's selective regulation of apoptosis. Rb has been reported to suppress the expression of cell-death regulatory genes, and it is also known that TNF-α-induced killing does not require new gene expression. So, together, this indicates that Rb's function in apoptosis can be independent of gene transcription.