The cell cycle, the process by which a cell divides, must be precisely controlled to maintain tissue structure and health. This control is necessary for development, wound healing, and replacing old or damaged cells. The cell cycle is regulated by two primary classes of factors: external signals that originate outside the cell, and internal mechanisms that operate within the cell itself. These regulatory factors work together to ensure that cell proliferation occurs only when appropriate for the organism.
External Control Signals
External control signals are messages that originate from the environment outside the cell and influence the decision to divide. These signals often come from neighboring cells or are transported through the bloodstream. They act as initial “go” or “stop” cues based on the body’s overall needs and the local tissue context.
One common positive external signal is the presence of growth factors, which are proteins or hormones released by certain cells. For example, Platelet-Derived Growth Factor (PDGF) is released by platelets at a wound site, stimulating the division of fibroblasts to repair the damage. These factors bind to specific cell surface receptors, initiating internal events that encourage the cell to begin division.
Cells also respond to physical cues from their surroundings, which serve as negative external controls. Density-dependent inhibition causes cells to stop dividing once they physically touch their neighbors, ensuring they form a single, orderly layer. Furthermore, most normal cells exhibit anchorage dependence, meaning they must be attached to a surface or the extracellular matrix to receive signals to divide.
Internal Checkpoints and Molecular Control
Internal regulators are molecules that function inside the cell to ensure the cell cycle processes are completed accurately and in the correct sequence. These molecules act as a quality control system, pausing the cycle at specific checkpoints until all conditions are met.
The core molecular drivers of this internal timing system are cyclins and their partner enzymes, the Cyclin-Dependent Kinases (CDKs). CDK enzymes are always present but are inactive unless bound to a corresponding cyclin protein. Cyclin concentrations fluctuate throughout the cell cycle, activating different CDKs at specific phases.
When a cyclin binds to a CDK, the complex becomes an active enzyme that phosphorylates specific target proteins inside the cell. Phosphorylation acts like a switch, activating or deactivating proteins required to progress to the next phase, such as DNA replication or chromosome separation. The cell cycle includes three main checkpoints where this molecular machinery is regulated.
The G1 checkpoint is the primary restriction point, checking for adequate cell size, sufficient nutrients, and DNA damage before committing to replication. The G2 checkpoint occurs before entry into mitosis, ensuring the entire genome has been accurately replicated and is undamaged. The M checkpoint, or spindle checkpoint, operates during mitosis to confirm that all chromosomes are correctly attached to the spindle fibers. This prevents the unequal distribution of genetic material to the daughter cells.
Consequences of Dysregulation
The failure of both external and internal controls is a defining feature of unregulated cell growth. When cells lose their ability to respond to external stop signals, such as density-dependent inhibition, they continue to divide even when tightly crowded. This allows a cell population to expand beyond the boundaries dictated by tissue needs.
Failure of the internal regulatory mechanisms is often more catastrophic, as it leads to the propagation of genetic errors. A common example involves the tumor suppressor gene p53, which acts as a guardian of the genome. When p53 detects DNA damage, it triggers the production of the protein p21, which inhibits the activity of Cdk/cyclin complexes. This pathway halts the cell cycle at the G1 checkpoint, allowing time for DNA repair. If the damage is irreparable, p53 can initiate programmed cell death to prevent the damaged cell from dividing.
Mutations that inactivate the p53 gene allow cells with damaged DNA to bypass the G1 and G2 checkpoints entirely. This leads to uncontrolled proliferation and genomic instability, which are hallmarks of cancerous transformation.