E2F and the molecular mechanisms of early cell-cycle control.

This is an exciting era in cell-cycle research. We are now uncovering the molecular details of a critical pathway which regulates early cell-cycle progression by integrating signals emanating from proteins that drive the cell cycle with the transcription apparatus and the consequent control of target genes. Molecules that function to positively regulate, such as cyclin-cdk complexes, and negatively regulate, such as the cdk inhibitors, converge on the pathway and, in turn, regulate the activity of pRb and related proteins. A principal role of pRb is in the regulation of the E2F family of transcription factors, and activity of which determines cell-cycle progression. Importantly, many of the proteins in this pathway are encoded by genes which are frequently mutated in tumour cells, a feature which emphasizes the pathway's critical role in orchestrating early cell-cycle control. In fact, it seems likely that the pathway is, at some point, aberrantly regulated in most, if not all, human tumour cells. It is principally E2F that pRb seeks out to exert its effect on the cell cycle. However, it is unclear why there is such a plethora of E2F/DP heterodimers under the E2F umbrella: different genes, different targets or different pathways of control? In human tumour cells, why is Rb so frequently mutated, whereas the genes encoding p107 and p130 apparently not so? Does this imply that the physiological roles of p107 and p130 are of overwhelming importance that cells cannot accommodate mutation in either gene, or do they take on such minor roles that their mutation in tumour cells would be of incidental consequence? These questions, and many others, remain to be resolved. Finally, we should never forget that the increasing knowledge of cell-cycle control has profound implications for the treatment of proliferative disease. The progress and insights into the physiological pathways which regulate cell-cycle progression offer a new and exciting range of realistic targets through which oncogenesis may, in the near future, be effectively treated. The mechanistic and structural information that is rapidly accumulating offers new promise in the search for small-molecule clinically viable drugs.