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 the “ ” learning card.
Abnormalities of the cell cycle that lead to the development of cancer are discussed in detail in the “ ” learning card.
- Definition: sequence of events that take place to enable DNA replication and cell division.
- The cell cycle is first 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.
G stands for Gap/Growth and S for Synthesis!
Definition: The interval between cell divisions in which the cell prepares for the next division. The duration of interphase varies and contains three phases (excluding the G0 phase):
- G1 phase : synthesis of RNA, proteins, and cell organelles
- S phase
- G2 phase :
- Resting period of a cell after exiting the cell cycle.
- Cell is differentiated and has a specific respective function but is no longer undergoing cell division.
- Only proliferating cells pass through the cell cycle. Most mature tissue cells are in the G0 phase.
- Certain cell types can enter the G1 phase from the G0 phase if stimulated
One of the features of malignant tumors is the 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 budding of the cellular body
- Duration: ∼1 h
- 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)
5 Phases of mitosis
Proper functioning of the mitotic spindle is a prerequisite for chromosome transportation. Inhibition with spindle poison 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 into the S phase by binding to tyrosine kinase receptors.
- Checkpoints: There are defined checkpoints and transition points at various points in the cell cycle (see details below).
- Cyclin-dependent kinase (CDK): A normally inactive kinase that needs to be activated to enable transition from one phase of the cell cycle to the other.
- Cyclins: regulatory proteins that activate CDKs, thus regulating the cell cycle
- Cyclin-CDK complexes: Complex proteins that phosphorylate other proteins to regulate the progression of the cell cycle. These enzymes must be activated and inactivated at specific points of the cell cycle to allow for normal progression of the cell cycle.
Tumor suppressors: Proteins that arrest and modulate (e.g., repair or induce apoptosis) the cell cycle of cells with an abnormal genome. Examples include
- BRCA-1/BRCA-2; : DNA repair proteins; defect associated with breast cancer
- NF1: defect associated with neurofibromatosis type 1
- p53: defect associated with Li-Fraumeni syndrome and most cancers
- APC: defect associated with familial adenomatous polyposis
- pRb: defect associated with retinoblastoma
- For a complete list, see
Important checkpoints and transition points
G1 checkpoint: A cell division checkpoint during the G1 phase that restricts entry into the synthesis (S) phase.
- After this checkpoint, cells become committed to division.
- Controls the cell's nuclear-cytoplasmic ratio, sufficient nutrient levels, and DNA damage
- Growth signals lift the checkpoint.
- DNA damage prevents division.
- Loss of this checkpoint (e.g., from loss of p53 function) leads to unregulated cell division.
Regulated by the p53 protein and the cyclin D/Cdk4 complex, which both affect the activity of the retinoblastoma protein (pRb).
- Cyclin D/Cdk4 complex: initiates DNA replication by inactivating pRb
p53: If DNA damage is present, it inhibits DNA replication by activating pRb and initiates apoptosis if DNA damage is not repaired (a tumor suppressor that is also called “the guardian of the genome”).
- p53 is 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
DNA damage → activation of protein kinases → phosphorylation of p53 → p53 activates various genes, for example:
- → activates p21 → p21 is a phosphoprotein that inhibits Cdks → Cdk-mediated phosphorylation of pRb is decreased → pRb becomes active and binds transcription factor E2F → entry into the S phase cannot occur (activation of the p27 protein from the same family leads to the same sequence of events)
- Proapoptotic active proteins of the Bcl-2 family such as Bax and Bad
- G2 checkpoint: A cell division checkpoint during the G2 phase.
- M checkpoint (Spindle checkpoint): checkpoint between metaphase and anaphase in mitosis.
|Labile cells|| |
|Quiescent (stable) cells|| |
|Permanent cells|| |
Abnormalities of the cell cycle that lead to the development of cancer are discussed in detail in the “” learning card.