Healthy cells decide when to divide through a tightly regulated cell-cycle control system that integrates internal and external signals to ensure division occurs only under appropriate conditions.
Key Mechanisms Controlling Cell Division
- Cyclin-Dependent Kinases (Cdks) and Cyclins:
The central regulators are Cdks, a family of protein kinases whose activity depends on binding to regulatory proteins called cyclins. Cyclins are synthesized and degraded cyclically during the cell cycle, causing oscillations in Cdk activity that trigger progression through different cell- cycle phases. For example, activation of S-phase cyclin-Cdk complexes initiates DNA replication, while M-phase cyclin-Cdk complexes trigger mitosis
- Phosphorylation and Proteolysis:
Cdks must be phosphorylated at specific sites to become fully active, and their activity can be inhibited by phosphorylation or binding of inhibitory proteins. Cyclins are degraded by ubiquitin-mediated proteolysis at precise cell-cycle stages, ensuring that Cdks are activated only when appropriate. Two key ubiquitin ligases, SCF and the anaphase-promoting complex (APC), regulate the destruction of cyclins and other cell-cycle regulators to control cycle progression
- Internal and External Regulatory Signals:
Internal regulators monitor the completion of key events within the cell, such as DNA replication and cell growth, before allowing progression. External regulators include growth factors and mitogens that signal the cell to divide only when environmental conditions are favorable. Cells sense these signals via receptors like receptor tyrosine kinases (RTKs), which initiate signaling pathways promoting cell division
- Checkpoints and Negative Regulators:
The cell cycle has checkpoints where negative regulators (e.g., proteins like p53, Rb, and p21) can halt progression if conditions are not met, such as DNA damage or incomplete replication, preventing faulty division
Decision Timing and Environmental Sensing
Recent research indicates that the decision for a cell to divide is influenced not only by signals received after a cell forms but also by the history of growth factor signaling during the mother cell’s cycle. The mother cell's exposure to mitogens affects whether its daughter cells will enter the cell cycle and divide, highlighting a memory effect in cell division decisions
. In summary, healthy cells decide when to divide by integrating cyclical activation of cyclin-Cdk complexes, regulated proteolysis, phosphorylation events, and signals from both inside and outside the cell. This complex control system ensures cells divide only when conditions are optimal, maintaining tissue health and preventing uncontrolled proliferation
