TOPICS & REFERENCES
• The cell cycle CHAPTER 5
• Cyclins and cyclin-dependent kinases
(cdks).
• Mechanisms of cdk regulation.
• Progression through the G1checkpoint.
• The G 2 checkpoint.
• The mitotic checkpoint.
• The cell cycle and cancer.
• Therapeutic strategies.
• Cyclin-dependent kinase inhibitors.
• Other cell cycle kinase inhibitors.
• Other cell cycle kinase targets.
• Inhibitors of the mitotic spindle.
The cell cycle
The cell cycle
• Each cell can reproduce to form two daughter cells, and so on;
• Thus cell reproduction is cyclic.
• The sequence of stages through which a cell passes between one
cell division and the next is called the cell cycle and is made
up of four stages: G1, S phase, G2, M phase.
• G1, S, and G2 make up the part of the cycle called interphase.
• The genetic material of a cell is replicated in S phase (DNA
synthesis).
• M phase involves the partitioning of the cell to produce two
daughter cells and includes mitosis and cytokinesis.
Cyclins and cyclin-dependent kinases
(cdks).
Most cells in an adult are not in the process of cell division. They are quiescent
and enter an inactive period called G0, a phase outside of the cell cycle.
Mitogens or growth factors can, however, induce cells in G0 to re-enter the
cell cycle and pass a control point called the G1 restriction point.
The passage of the cell through the different phases of the cell cycle is coordinated and
regulated by a set of proteins called cyclins and their associated cyclin- dependent
kinases (cdks).
Cyclins were so named because of the cyclical changes in their concentrations
that occur over a series of cell divisions.
The concentration of cyclin protein is dependent on the transcription of its gene
and by subsequent regulated protein degradation.
Different cyclin–cdk complexes are present at specific points in the cell cycle
and are important regulators of irreversible phase transitions
Mechanisms of cdk regulation
There are four mechanisms of cdk
regulation:
1. Association with cyclins,
2. Association with cdk inhibitors,
3. Addition of phosphate groups that
activate cdk activity
4. Addition of phosphate groups that
inhibit cdk activity
Cell cycle checkpoints
• Cell cycle checkpoints a series of biochemical signaling pathways
that sense and induce a cellular response to DNA damage, are
important for maintaining the integrity of the genome.
• The G1 checkpoint leads to the arrest of the cell cycle in response to
DNA damage, ensuring that DNA damage is not replicated during S
phase.
• The G2 checkpoint leads to the arrest of the cell cycle in response to
damaged and/or unreplicated DNA to ensure proper completion of S
phase.
• The M checkpoint leads to the arrest of chromosomal segregation in
response to misalignment on the mitotic spindle.
The cell cycle and cancer
• Genes encoding cell cycle regulators are
frequently mutated in human tumors leading to
aberrant regulation of the cell cycle,
unscheduled proliferation, and carcinogenesis.
• Mutations in CDK genes found in cancer cells
have been well characterized. For example, a
miscoding mutation (Arg24Cys) in CDK4 blocks
binding to INK4 inhibitors in a subset of
melanoma patients.
The G2 checkpoint
• The G2 checkpoint blocks
entry into M phase in cells
that have incurred DNA
damage in previous phases
or have not correctly
completed S phase. DNA
damage activates either of
two kinases, ATM or ATR.
These kinases then
phosphorylate and activate
checkpoint kinases Chk1
and Chk2
RB protein
• A key substrate of the cyclin D–cdk 4/6 complex is
the RB protein
• RB serves as a molecular link for the G1–S phase
transition.
• RB does not bind to specifi c DNA sequences but
instead regulates the activity of the E2F
transcription factor family, which is crucial for the
expression of genes needed for S phase.
• The activity of RB is regulated by sequential
phosphorylation events by cyclin– cdks.
Therapeutic strategies
