ACTIVITY OF THE RETINOBLASTOMA FAMILY PROTEINS, PRB, P107, AND P130, DURING CELLULAR PROLIFERATION AND DIFFERENTIATION

Genetic evidence from retinoblastoma patients and experiments describi ng the mechanism of cellular transformation by the DNA tumor viruses h ave defined a central role for the retinoblastoma protein (pRB) family of tumor suppressors in the normal regulation of the eukaryotic cell cycle. These proteins, pRB, p107, and p130, act in a cell cycle-depend ent manner to regulate the activity of a number of important cellular transcription factors, such as the E2F-family, which in turn regulate expression of genes whose products are important for cell cycle progre ssion. In addition, inhibition of E2F activity by the pRB family prote ins is required for cell cycle exit after terminal differentiation or nutrient depletion. The loss of functional pRB, due to mutation of bot h RB1 alleles, results in deregulated E2F activity and a predispositio n to specific malignancies. Similarly, inactivation of the pRB family by the transforming proteins of the DNA tumor viruses overcomes cellul ar quiescence and prevents terminal differentiation by blocking the in teraction of pRB, p107, and p130 with the E2F proteins, leading to cel l cycle progression and, ultimately, cellular transformation. Together these two lines of evidence implicate the pRB family of negative cell cycle regulators and the E2F family of transcription factors as centr al components in the cell cycle machinery.