Figure 4. Mechanisms of pRb inactivation in human cancer.

Three main mechanisms of pRb inactivation are observed in human cancer, and these mechanisms are not randomly distributed. Rb1 mutation is common in some cancers, but rare in others. Likewise, inactivation by deregulated pRb phosphorylation is common in a distinct subset of human cancers, but Rb1 mutation is rarely observed in this subset. The model proposes that each mechanism of inactivation has different molecular and functional consequences. Deregulated pocket protein phosphorylation is proposed to abrogate some protein interactions but not others. Coupled with considerations of the pocket protein interaction network outlined in Figure 3, different cell types may select for different mechanisms of pRb inactivation because the molecular consequences are more favorable for carcinogenesis.