Figure 1. The retinoblastoma (Rb) tumor suppressor pathway.

p16^INK4A inhibits CDK4/6 This overrides growth signals and results in G1 growth arrest and senescence (upper panel). The high-risk HPV E7 proteins, which trigger p16^INK4A expression, have evolved to overcome this response by targeting Rb for degradation. Under these conditions, p16^INK4A expression and CDK4/6 inhibition is required for cell survival. Hence p16^INK4A, which normally functions as a tumor suppressor (red) now has oncogenic activities (green) and similarly, CDK4/6, which normally are oncogenic (green) are now tumor suppressive (red), demonstrating the biological activities of key components of the retinoblastoma tumor suppressor pathway are dependent on the cellular context (see text for details).