 |
The remarkable pace of cell-cycle research over the last two decades has led to the model of eukaryotic cell-cycle control outlined in Figure 13-2. A beautiful logic underlies these molecular controls. Each regulatory event has two important functions: to activate a step of the cell cycle and to prepare the cell for the next event of the cycle. This strategy ensures that the phases of the cycle occur in the proper order. DNA replication is activated by G1 Cdks, which stimulate the transcription of S-phase Cdk components and induce degradation of the S-phase inhibitor. G1 Cdks also prepare cells for mitosis by inactivating the APC and allowing mitotic cyclins to accumulate. Mitosis is triggered by mitotic Cdk activity, which induces chromosome condensation, assembly of the mitotic spindle, and attachment of metaphase chromosomes to spindle fibers resulting in metaphase. Mitotic Cdks also carry out activation of the APC, which is required for initiating anaphase and the degradation of mitotic cyclins. The resulting decrease in mitotic Cdk activity not only allows exit from mitosis but also permits assembly of DNA pre-replication complexes and expression of G1 cyclins, thus initiating another cycle.
Although the general logic of cell-cycle regulation now seems well established, many critical details remain to be discovered. The components of the pre-replication complex that must be phosphorylated by S-phase Cdk-cyclin complexes to initiate DNA replication remain to be determined, as does the mechanism of initiation. The targets of mitotic Cdk-cyclin activity that cause mitotic spindle assembly also remain to be characterized. Current understanding of the structure of condensed, mitotic chromosomes remains vague. Much remains to be learned about how the APC is activated during anaphase and how its activity is first directed toward anaphase inhibitors and only subsequently toward mitotic cyclins. Considerable progress has been made in understanding how DNA damage leads to G1 and G2 arrest, but the mechanisms by which the other two checkpoints operate are poorly understood.
Understanding these detailed aspects of
cell-cycle control will have significant consequences, particularly for the
treatment of cancers. Radiation therapy works because it causes DNA damage in the
target cells that induces their apoptosis. But this induced apoptosis depends on p53
function. For this reason, human cancers associated with mutations of both
p53 alleles, which is fairly common, are particularly resistant
to radiotherapy. If more were understood about cell-cycle controls and checkpoints,
new strategies for treating p53-minus cancers might be possible. For instance, some
chemotherapeutic agents inhibit microtubule function, interfering with mitosis.
Resistant cells selected during the course of treatment may be defective in the
mitotic checkpoint as the result of mutations in the genes encoding the proteins
involved. Can the loss of this checkpoint be turned to advantage? Only better
understanding of the molecular processes involved can answer the question.
A great deal remains to be learned about the control of cell replication during the development of multicellular organisms. Regulation of cell replication is of obvious importance for the proper structure and function of the organ systems of vertebrates. Not only is the timing of cell division crucial, but also the position of the plane of cell cleavage, which recapitulates the position of the metaphase plate. In many cases during development, cell division is highly asymmetric. How is this achieved? Clearly, there are many fundamental and significant questions yet to be answered concerning eukaryotic cell-cycle control.