Cell cycle-regulated and proliferation stimulus-responsive genes.

We have reviewed here genes whose expression may vary during the "cell cycle" and we discuss the underlying regulatory mechanisms. Given a correlation between the cell cycle and expression of a particular gene, the question arises whether that gene regulates the cycle, whether the cycle regulates that gene, or whether the correlation is simply the consequence that both the cell cycle and that gene respond to the same signal(s). Gene expression is regulated at diverse levels, and the relative importance of regulation at these different levels depends on which version of the cell cycle one has in mind; depending upon the context, the concept of the (higher eukaryote) cell cycle has a number of different operational meanings. Thus the first few divisions of the fertilized egg consist of successive S and M phases, with insignificant G1 and G2 phases, regulated entirely at the translational and post-translational level by the phosphorylation/dephosphorylation of p34cdc2 and the synthesis/degradation of one or more cyclins-keyed perhaps to the cytoplasm/nucleoplasm ratio and the completion of DNA replication. In contrast, cells stimulated to exit quiescence, (G0), require new gene transcription and changes in the post-transcriptional control of gene expression. Cells proliferating in a constant environment proceed directly from mitosis into G1 and are less dependent on (but not independent of) new transcription; here controls at the post-transcriptional and post-translational levels are more pronounced. In addition to regulation by p34cdc2, input from cell-specific growth factors or other extracellular signals is essential for most untransformed cells to continue through the cycle. Many transformed cells in contrast do not require exogenous signals and are altered in the way that key regulatory genes (e.g., p53, RB) are controlled. While cells of many lower eukaryotes appear capable of an indefinite number of cell cycles, the typical higher eukaryotic cell appears to have a limit on this number--untransformed, nonestablished vertebrate cells are usually mortal. For unknown reasons, established cell lines and certain embryonic or stem cells under the right conditions, are immortal and capable of indefinite proliferation. Apparently, the price paid to construct a differentiated multicellular organism is a limit on the number of cell divisions that the constituent somatic cells are capable of undergoing.