Control of the Cell Cycle (fi gure 10.18)
Research uncovered cell cycle control factors.
Experiments showed that there are positive regulators of mitosis,
and that there are proteins produced in synchrony with the cell
cycle (cyclins). The positive regulators are cyclin-dependent kinases
(Cdks). Cdks are complexes of a kinase and a regulatory molecule
called cyclin. They phosphorylate proteins to drive the cell cycle.
The cell cycle can be halted at three checkpoints.
Checkpoints are points at which the cell can assess the accuracy
of the process and stop if needed. The G1/S checkpoint is a
commitment to divide; the G2/M checkpoint ensures DNA integrity;
and the spindle checkpoint ensures that all chromosomes are
attached to spindle fi bers, with bipolar orientation.
Cyclin-dependent kinases drive the cell cycle.
The cycle progresses by the action of Cdks. Yeast have only one
CDK enzyme; vertebrates have more than four enzymes. During the
G1 phase, G1 cyclin combines with Cdc2 kinase to form the Cdk that
triggers entry into S phase.
The anaphase-promoting complex/cyclosome (APC/C) activates a
protease that removes cohesins holding the centromeres of sister
chromatids together; the result is to trigger anaphase, separating the
chromatids and drawing them to opposite poles. The APC/C also
triggers destruction of mitotic cyclins to exit mitosis.
In multicellular eukaryotes, many Cdks and external signals
act on the cell cycle.
Growth factors, like platelet-derived growth factor (PDGF),
stimulate cell division. This acts through a MAP kinase cascade
that results in the production of cyclins and activation of Cdks to
stimulate cell division in fi broblasts after tissue injury.
Cancer is a failure of cell cycle control.
Mutations in proto-oncogenes have dominant, gain-of-function
effects leading to cancer. Mutations in tumor-suppressor genes are
recessive; loss of function of both copies leads to cancer.