Control of the Cell Cycle
Summary of Key Points
• Most cells in postnatal tissues are quiescent. Exceptions include abundant cells of the hematopoietic system, skin, and gastrointestinal mucosa, as well as other minor progenitor populations in other tissues.
• Many quiescent cells can reenter into the cell cycle with the appropriate stimuli, and the control of this process is essential for tissue homeostasis.
• The key challenges for proliferating cells are to make an accurate copy of the 3 billion bases of DNA (S phase) and to segregate the duplicated chromosomes equally into daughter cells (mitosis).
• Progression through the cell cycle is dependent on both intrinsic and extrinsic factors, such as growth factor or cytokine exposure, cell-to-cell contact, and basement membrane attachments.
• The internal cell cycle machinery is controlled largely by oscillating levels of cyclin proteins and by modulation of cyclin-dependent kinase (Cdk) activity. One way in which growth factors regulate cell cycle progression is by affecting the levels of the D-type cyclins, Cdk activity, and the function of the retinoblastoma protein.
• Cell cycle checkpoints are surveillance mechanisms that link the rate of cell cycle transitions to the timely and accurate completion of prior dependent events. p53 is a checkpoint protein that induces cell cycle arrest, senescence, or death in response to cellular stress.
• Checkpoints minimize replication and segregation of damaged DNA or the abnormal segregation of chromosomes to daughter cells, thus protecting cells against genome instability.
• Disruption of cell cycle controls is a hallmark of all malignant cells. Frequent tumor-associated alterations include aberrations in growth factor signaling pathways, dysregulation of the core cell cycle machinery, and/or disruption of cell cycle checkpoint controls.
• Because cell cycle control is disrupted in virtually all tumor types, the cell cycle machinery provides multiple therapeutic opportunities.
1. Which statement best describes the function of the retinoblastoma protein?
2. Checkpoint abrogation is a therapeutic strategy based on the inhibition of checkpoint proteins. What is the major difference between inhibiting basic cell cycle regulators versus inhibiting checkpoint regulators for cancer therapy?
A Checkpoint abrogation specifically arrests cells in S-phase or in mitosis.
B Checkpoint abrogation eliminates the function of the checkpoint and cell arrest before the G1/S or the G2/M transitions.
C The inhibition of checkpoint proteins results in lack of negative controls and promotes cell proliferation, whereas the inhibition of basic cell cycle regulators promotes cell death.
D The inhibition of checkpoint regulators results in the accumulation of damage in proliferating cells, and this strategy exploits the deleterious effect of this damage.
3. Most cancers are aneuploid or present chromosomal instability (CIN). What are the consequences of having a high rate of chromosome gains and losses for tumor development?
A CIN favors tumor development by increasing the levels of oncogenes.
B CIN favors tumor development by decreasing the levels of tumor suppressors.
C CIN may have both positive and negative consequences in tumor development, but the heterogeneity of cell karyotypes may allow a selection for cells with oncogenic properties.
D CIN is deleterious for the tumor because most tumors cells will harbor karyotypes that are incompatible for cell survival.
1. Answer: B. Of the choices offered, B is the best description of the retinoblastoma protein; it represses transcription of cell cycle genes by inhibiting E2F transcription factors and by recruiting chromatin remodeling complexes to specific promoters.
2. Answer: C. The inhibition of proteins required for cell cycle progression, such as cyclin-dependent kinases, results in cell cycle arrest because it impairs the transition to specific phases of the cell cycle. Targeted cells then may display a permanent arrest (senescence) or die of apoptosis. Inhibition of checkpoint proteins is not aimed at arresting cells but rather at allowing cells to progress through the cell cycle with damage. For instance, inhibition of the deoxyribonucleic acid damage regulators may allow cells to accumulate damage, and these cells are most sensitive to apoptosis in the presence of specific treatments. Inhibition of the spindle assembly checkpoint, on the other hand, results in the accumulation of massive numeric aberrations in the number of chromosomes and frequent mitotic catastrophe.
3. Answer: C. A, B, and D may be true, but C best describes the consequences of CIN. The high rates of instability may have both positive and negative consequences in the survival and proliferative properties of the cell. Eventually, clones with the most favorable combinations of chromosomes may have proliferative advantages and are selected during tumor development.
