PRB, P107 AND THE REGULATION OF THE E2F TRANSCRIPTION FACTOR

Small DNA tumor viruses, such as adenovirus, encode proteins that dere gulate the cell cycle. These proteins are potent transforming agents w hen tested in standard oncogenic assays. For adenovirus the best chara cterized viral oncoproteins are the early region 1A (E1A) products. Mu tational studies have shown that E1A's oncogenic ability is determined primarily by its ability to bind to certain cellular proteins and int erfere with their function. One of these cellular targets for E1A is t he product of the retinoblastoma tumor suppressor gene, pRB, pRB is a negative regulator of cell proliferation, and its inactivation has bee n shown to be an important oncogenic step in the development of many h uman 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 p hysically associating with key transcription factors. The best charact erized 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 ro les in the regulation of cell proliferation. During cell cycle progres sion, phosphorylation of pRB appears to change its conformation and E2 F is released. In pathogenic settings E2F transactivation is not regul ated by pRB binding. In human tumors with mutations in the retinoblast oma gene, functional pRB is absent and hence can no longer inhibit E2F activity. During adenovirus transformation, E1A binds to pRB and disp laces E2F. In both these cases, E2F is released from pRB-mediated regu lation at inappropriate times. The activation of these E2F-responsive genes may lead to the stimulation of cell proliferation. While we do n ot know whether E2F is the only target for pRB action, this work has f ormed a general picture of how tumor suppressor gene products such as pRB can control specific transcriptional events and act as negative re gulators of cell growth. Recent experiments have shown that E2F repres ents the combined activity of an extensive series of protein complexes . There are at least five genes that encode E2F polypeptides, and prob ably several more have yet to be identified. The E2F transcription fac tor 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 D P family. Intriguingly DP and E2F genes are also found in Drosophila a nd these may provide alternative approaches to the investigation of E2 F function. In mammalian cells E2F/DP heterodimers are regulated, at l east 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/cd k2, and additional complexes exist that have yet to be fully character ized. These E2F complexes are detected at specific points of the cell cycle and appear to provide different elements of E2F regulation.