STABLE BINDING TO E2F IS NOT REQUIRED FOR THE RETINOBLASTOMA PROTEIN TO ACTIVATE TRANSCRIPTION, PROMOTE DIFFERENTIATION, AND SUPPRESS TUMOR-CELL GROWTH

The retinoblastoma tumor suppressor protein (pRB) can inhibit cell cyc le progression and promote differentiation. pRB interacts with a varie ty of transcription factors, including members of the E2F and C-EBP pr otein families and MyoD, and can either repress or activate transcript ion depending on the promoter under study. These biological and bioche mical activities of pRB have been mapped previously to a core domain, referred to as the pRB pocket. Using a panel of synthetic pRB pocket m utants, we found that the acute induction of a G(1)/S block by pRB is linked to its ability to both bind to E2F and to repress transcription . In contrast, these functions were not required for pRB to promote di fferentiation, which correlated with its ability to activate transcrip tion in concert with fate-determining proteins such as MyoD. All tumor -derived PRE mutants tested to date failed to bind to E2F and did not repress transcription. Despite an inability to bind to E2F, pRB mutant s associated with a low risk of retinoblastoma, unlike high-risk mutan ts, retained the ability to activate transcription and promote differe ntiation. Thus, the pRB pocket participates in dual tumor suppressor f unctions, one linked to cell cycle progression and the other to differ entiation control, and these functions can be genetically and mechanis tically dissociated.