Cell cycle: regulatory events in G1-->S transition of mammalian cells.

A cell divides into two daughter cells by progressing serially through the precisely controlled G1, S, G2, and M phases of the cell cycle. The crossing of the G1/S border, which is marked by the initiation of DNA synthesis, represents commitment to division into two complete cells. Beyond this critical point no further external signals are required. We now have more comprehensive knowledge of the temporal sequence of systems at this key transition from G1 to S--growth factor responses, a cascade of kinase reactions, activation of cyclins and their associated kinases, and oncogene and tumor suppressor gene products. Furthermore, we know that the absolute requirement for calcium and the timing of events associated with calmodulin and the 68 kDa calmodulin-binding protein are consistent with overall Ca++/calmodulin control of all steps from the response to growth factors in G1 to DNA replication in S phase. We now have to sort out the inter-relationships of myriad control proteins and their relation to the Ca++/calmodulin-dependent controls--Which are causes? Which are effects? And which are parallel processes? The answers will be important, as they represent both a much deeper understanding of this key process of life and an important opportunity for improving therapeutic medicine.