10.3 Control of the Cell Cycle

Cell Cycle Regulation

Regulation of the Cell Cycle

The cell cycle is controlled by both internal and external factors that determine whether a cell divides, pauses, or stops altogether. Internal regulators work from within the cell, while external signals come from the cell's environment.

Internal factors regulate cell cycle progression from within the cell:

• Cyclins and cyclin-dependent kinases (CDKs) control transitions between cell cycle stages. Cyclins bind to and activate CDKs, which then phosphorylate target proteins to push the cell forward. Different cyclin-CDK complexes are active at specific stages (G1, S, G2, M).
• Tumor suppressor genes like p53 monitor DNA integrity. If DNA damage is detected, p53 can halt the cell cycle to allow time for repair. Think of p53 as a brake pedal for cell division.
• Proto-oncogenes like Ras promote cell division when activated by growth signals. If a proto-oncogene becomes mutated or overexpressed, it turns into an oncogene, which drives uncontrolled cell division and can lead to cancer.

External factors regulate cell cycle progression from outside the cell:

• Growth factors (such as epidermal growth factor) bind to cell surface receptors and stimulate progression through the G1 phase.
• Contact inhibition causes cells to stop dividing when they become crowded and physically touch neighboring cells. Cancer cells typically lose this property.
• Anchorage dependence requires most normal cells to be attached to a surface (via integrins binding to extracellular matrix components) before they can divide.
• Nutrient availability of molecules like glucose and amino acids is necessary because cells need sufficient raw materials for energy production and biosynthesis during division.

Key Cell Cycle Checkpoints

Checkpoints are surveillance mechanisms that verify conditions are correct before the cell moves to the next phase. If something is wrong, the checkpoint halts progression until the problem is fixed or the cell is directed toward death.

• G1 checkpoint (restriction point): Checks for adequate cell size, nutrient availability, and absence of DNA damage before the cell commits to entering S phase. Once a cell passes this point, it's committed to dividing.
• G2/M checkpoint: Confirms that DNA replication is complete and accurate before the cell enters mitosis. Any remaining DNA damage is caught here.
• Metaphase checkpoint (spindle assembly checkpoint): Prevents the onset of anaphase until every kinetochore is properly attached to spindle microtubules. Once all chromosomes are correctly aligned, the anaphase-promoting complex (APC) is activated, which triggers the separation of sister chromatids.

These checkpoints are critical for maintaining genomic stability. Without them, cells could divide with damaged DNA, incomplete replication, or misaligned chromosomes, all of which can lead to mutations or abnormal chromosome numbers.

Cyclins and Cyclin-Dependent Kinases

CDKs are the engines of the cell cycle, but they can't work alone. They need cyclins to activate them.

CDKs are serine/threonine protein kinases that phosphorylate target proteins to regulate their activity. On their own, CDKs are inactive.

Cyclins are regulatory proteins whose levels rise and fall throughout the cell cycle. They are synthesized when needed and degraded when their job is done. This fluctuation is what gives the cell cycle its directional momentum.

When a cyclin binds its CDK partner, the resulting cyclin-CDK complex drives a specific cell cycle transition:

1. G1/S transition: Cyclin D pairs with CDK4/CDK6. This complex phosphorylates the retinoblastoma protein (Rb), which releases the transcription factor E2F. E2F then activates genes required for DNA replication in S phase.
2. S phase progression: Cyclin A pairs with CDK2 to promote ongoing DNA replication.
3. Entry into mitosis: Cyclin B pairs with CDK1. This complex phosphorylates substrates involved in nuclear envelope breakdown, chromosome condensation, and spindle assembly.

How cyclin-CDK activity is turned off:

• CKIs (cyclin-dependent kinase inhibitors) like p21 and p27 bind directly to cyclin-CDK complexes and block their activity. For example, when p53 detects DNA damage, it activates p21, which inhibits cyclin-CDK complexes and halts the cell cycle.
• Ubiquitin-mediated proteolysis tags cyclins with ubiquitin, marking them for destruction by the proteasome. This allows rapid inactivation of cyclin-CDK complexes at precise points in the cycle.

Cell Cycle Phases and Cellular Processes

• Interphase consists of G1 (cell growth), S (DNA replication), and G2 (preparation for division). The cell spends most of its life in interphase.
• Mitosis (M phase) is nuclear division, where duplicated chromosomes are separated into two identical nuclei.
• Cytokinesis is the division of the cytoplasm, producing two separate daughter cells.

Cell Cycle Exit and Cellular Fates

Not every cell keeps cycling. Cells can exit the cell cycle in two notable ways:

• Apoptosis is programmed cell death. It can be triggered by severe DNA damage or other stresses that are beyond repair. The cell dismantles itself in an orderly way, and its components are recycled by neighboring cells.
• Senescence is a state of permanent cell cycle arrest. It can be triggered by telomere shortening (after many rounds of division) or by cellular stress. Senescent cells remain alive and metabolically active but never divide again.