PRB, P107 AND THE REGULATION OF THE E2F TRANSCRIPTION FACTOR

Small DNA tumor viruses, such as adenovirus, encode proteins that deregulate the cell cycle. These proteins are potent transforming agents when tested in standard oncogenic assays. For adenovirus the best characterized viral oncoproteins are the early region 1A (E1A) products. Mutational studies have shown that E1A's oncogenic ability is determined primarily by its ability to bind to certain cellular proteins and interfere with their function. One of these cellular targets for E1A is the product of the retinoblastoma tumor suppressor gene, pRB, pRB is a negative regulator of cell proliferation, and its inactivation has been shown to be an important oncogenic step in the development of many human cancers. In adenovirus-mediated transformation, E1A binds to PRE and inactivates it, thus functionally mimicking the loss of pRB often seen in human tumors. There is now compelling evidence to suggest that pRB regulates transcription at specific phases of the cell cycle by physically associating with key transcription factors. The best characterized target of pRB is the transcription factor E2F. The interaction of pRB and E2F leads to the inhibition of E2F-mediated transactivation. Most of the genes that are known to be controlled by E2F have key roles in the regulation of cell proliferation. During cell cycle progression, phosphorylation of pRB appears to change its conformation and E2F is released. In pathogenic settings E2F transactivation is not regulated by pRB binding. In human tumors with mutations in the retinoblastoma gene, functional pRB is absent and hence can no longer inhibit E2F activity. During adenovirus transformation, E1A binds to pRB and displaces E2F. In both these cases, E2F is released from pRB-mediated regulation at inappropriate times. The activation of these E2F-responsive genes may lead to the stimulation of cell proliferation. While we do not know whether E2F is the only target for pRB action, this work has formed a general picture of how tumor suppressor gene products such as pRB can control specific transcriptional events and act as negative regulators of cell growth. Recent experiments have shown that E2F represents the combined activity of an extensive series of protein complexes. There are at least five genes that encode E2F polypeptides, and probably several more have yet to be identified. The E2F transcription factor is a heterodimer composed of two related polypeptides, one encoded by a member of the E2F gene family and the other by a member of the DP family. Intriguingly DP and E2F genes are also found in Drosophila and these may provide alternative approaches to the investigation of E2F function. In mammalian cells E2F/DP heterodimers are regulated, at least in part, by the formation of many larger complexes. E2F is found in separate complexes with pRB, p107/cyclin A/cdk2 or p107/cyclin E/cdk2, and additional complexes exist that have yet to be fully characterized. These E2F complexes are detected at specific points of the cell cycle and appear to provide different elements of E2F regulation.