The cell cycle is the sequence of events that take place to enable DNA replication and cell division. It can be divided into two phases: interphase and mitosis. Interphase is further divided into the G1 (gap 1), S (synthesis), and G2 (gap 2) phases, which prepare the cell for division. In mitosis, the single cell is dividing into two identical daughter cells. The cell cycle is subject to strict controls that prevent cells with damaged or faulty DNA from further dividing and passing on defects to daughter cells. Controlled cell death (apoptosis) is initiated if the DNA damage is irreparable. Disorders of these regulatory mechanisms play an important role in carcinogenesis.
The mechanisms forare discussed in “ :”
Abnormalities of the cell cycle that lead to the development of cancer are discussed in detail in “ .”
- Definition: the sequence of events through which cell growth, DNA replication, and cell division occur
G stands for Gap/Growth and S for Synthesis.
- Definition: the interval between cell divisions in which the cell prepares for the next division
- Duration: variable
3 phases of interphase (excluding the G0 phase)
- G1 phase (several hours to months)
- S phase (∼ 8 h)
- G2 phase (∼ 2–5 h)
G0 phase (resting phase)
- Definition: a resting phase which a cell enters after exiting the cell cycle from the G1 phase
- Duration: variable
- Cells that enter the G0 phase are differentiated, have specific functions, and are no longer undergoing cell division.
- Most mature tissue cells are in the G0 phase.
- Certain cell types reenter the G1 phase after the G0 phase when exposed to certain stimuli (e.g., hepatocyte proliferation after hepatectomy).
One of the features of malignant tumors is the high mitotic rate and dedifferentiation of tumor cells (i.e., reversal to less differentiated cells with a high mitotic rate). Multiple mitotic figures seen on microscopy are indicative of a malignant process.
- Definition: the process of cell division from the distribution of DNA to the budding of a cellular body
- Duration: ∼1 h (shortest phase of the cell cycle)
- Definition: the final phase of the cell cycle, following the replication of DNA
5 phases of mitosis
- Metaphase: maximal condensation of the chromosomes, which are aligned along the equatorial plane of the cell
- Mitotic index: the ratio of the number of cells undergoing mitosis to the total number of cells in the given population (e.g., per 1,000 cells or per microscopic area in the specimen)
Proper functioning of the mitotic spindle is a prerequisite for chromosome transportation. Inhibition with spindle poisons leads to arrest of mitosis and cessation of cell division. Spindle poisons include colchicine, which inhibits microtubule polymerization, as well as vinca alkaloids and taxanes.
Basic principles of cell cycle regulation
S phase initiation
- Certain growth factors (e.g., insulin, EGF, EPO, PDGF) stimulate the cell to go from G1 phase into the S phase by binding to tyrosine kinase receptors.
- Epidermal growth factor inhibitors (EGFRi) such as (used in nonsmall cell lung cancer) and (used in colorectal cancer and head/neck cancer) block the progression of a cell from the G1 phase to the S phase.
Cyclin-dependent kinase (CDK)
- A type of inactive kinase that must be activated to enable the transition from one phase of the cell cycle to the next
- Present throughout the entire cell cycle
- Activated via binding of cyclins to form
- Inhibited by cyclin-dependent kinase inhibitor proteins (CDKIs) if any errors in the genome are detected
- A group of regulatory proteins that activate CDKs and, therefore, play an important role in controlling the cell cycle
There are specific cyclins for specific phases of the cell cycle.
- Cyclin A: a protein that regulates cell cycle transition by binding to cyclin-dependent kinases (CDKs) 1 and 2.
- Cyclin B: a component of mitosis promoting factor, a cyclin-CDK complex that regulates the G2 checkpoint of the cell cycle
- A protein that regulates cell cycle transition by binding to cyclin-dependent kinases (CDKs) 3 and 8
- The cyclin C-CDK3 complex allows the transition from the G0 to the G1 phase, and the cyclin C-CDK8 complex regulates gene transcription by phosphorylating transcription factors and RNA polymerase II.
- Cyclin D
- Cyclin E: a protein that regulates the transition from the G1 to the S phase of the cell cycle by binding to cyclin-dependent kinase 2 (CDK2) and activating it
- Cyclin-CDK complexes
- A group of proteins that arrest and modulate (e.g., repair or induce apoptosis) the cell cycle of cells with an abnormal genome
- DNA mutations can lead to defective tumor suppressor genes allowing cells to divide uncontrollably.
- See “” for more information.
Important checkpoints and transition points
- Definition: : A cell cycle checkpoint is a specific point in time that marks the transition from one cell cycle phase to another during which the current condition of a cell is revised (i.e., if all requirements for the transition to the next phase are met)
- Definition: a cell division checkpoint during the G1 phase that restricts entry into the S phase
- Cyclin D/Cdk4 complex
p53 tumor suppressor
- A protein that inhibits DNA replication by activating pRb and initiates apoptosis of the cells with irreparable DNA damage
- DNA damage → activation of protein kinases → phosphorylation of p53 → activation of p21 → inhibition of Cdks → inhibition of Cdk-mediated phosphorylation of pRb → pRb activation and binding of transcription factor E2F → cell arrest in the G1 phase (no entry into the S phase)
- Activation of the p27 protein (a phosphoprotein that prevents cell cycle progression by inhibiting cyclin/cyclin-dependent kinase complexes) leads to the same sequence of events.
- Present in every cell but undergoes continuous ubiquitylation and degradation
- Phosphorylated p53 can no longer be ubiquitinylated and degraded, leaving it free to act as a transcription factor.
- Proapoptotic active proteins of the Bcl-2 family such as Bax and Bak
- Definition: a cell division checkpoint during the G2 phase
- Regulation: mitosis promoting factor (MPF), which is composed of Cdk1 and cyclin B
M checkpoint (spindle checkpoint)
- Definition: a checkpoint between metaphase and anaphase in mitosis
- Characteristics: ensures correct alignment of the chromosomes and sister chromatids at the equatorial plane before the separation of sister chromatids
|Cell types by replication properties|
|Quiescent (stable) cells|