The Mechanism of Action of the Retinoblastoma Gene Product

It is has now been over 20 years since Knudson proposed that mutation in the retinoblastoma (Rb) gene is the genetic basis of the rare recessive childhood cancer, retinoblastoma (Knudson 1971). Since then, the Rb gene product (pRb) has established itself as a protein of central importance to those researchers interested in the regulation of cellular proliferation and the mechanisms of cellular transformation. Its biological properties do, however, differ in one important respect from the dominant growth-promoting effects of the ever expanding plethora of proto-oncogenes because it affects proliferation negatively, rather than positively. Thus, pRb has been labelled a tumour suppressor or anti-oncogene. Accordingly, the Rb gene is frequently mutated in tumour cells isolated from a variety of sources and pRb is sequestered by certain viral oncoproteins, effects that are assumed to inactivate its growth-regulating properties. Despite a wealth of information, however, its mechanism of action has remained an enigma. The purpose of this review is to collate recent developments in the field that now suggest a mechanism for how pRb exerts the biological effects of negative growth control.