Alterations in G1/S Cell‐Cycle Control Contributing to Carcinogenesis

Mutations involving the retinoblastoma tumor-suppressor gene (RB-1) have been described in a variety of human neoplasms. In addition, many tumors that retain a wild-type RB-1 allele harbor mutations that indirectly impair the function of the RB-1 gene product (pRB). pRB is a nuclear protein that regulates cell-cycle progression and, in at least certain tissues, differentiation. The former has been linked to its ability to form complexes with members of the E2F transcription factor family. E2F DNA-binding sites have been identified in the regulatory regions of a number of genes involved in cell-cycle progression. pRB-E2F complexes actively repress transcription when bound to these sites. All tumor-derived pRB mutants have lost the ability to bind to E2F. Conversely, activation of E2F-responsive genes is sufficient to overcome a pRB-induced cell-cycle block and, in certain cell types, can lead to transformation. Thus, E2F appears to be a physiologically relevant target of pRB action, and deregulation of E2F-responsive genes is a common, and possibly universal, step in human carcinogenesis.