Fundamental Processes - Overview of the Cell Cycle

Control of Cell Division

• Most cells have two major phases: mitosis and interphase often together referred to as the cell cycle
• For most tissues at any given time, only a few cells are in mitosis while the rest remain in interphase which is the period between divisions of the cytoplasm and is where a typical eukaryotic cell spends most of its life
• Some cells lose the capacity to divide altogether and stay in interphase indefinitely (for example in humans: nerve cells and muscle cells), while some divide regularly and others only occasionally

The Cell Cycle

Interphase consists of three sub-phases:

• G₁ is Gap 1 → the period just after mitosis and before the beginning of DNA synthesis
• S (synthesis) → which is the time when the cell’s DNA is replicated
• G₂ is Gap 2 → the time after S and prior to mitosis

Mitosis and cytokinesis are referred to as M-phase:

• the G₁→S transition commits the cell to enter another cell cycle

Cyclins and other proteins signal events in the cell cycle

• Transitions from G₁→S→G₂→M depend on activation of a protein called cyclin-dependent kinase, or Cdk (a kinase is an enzyme that transfers a phosphate from ATP to different protein(s) by a process called phosphorylation)
• Activated Cdk transfers phosphates from ATP to certain amino acids of proteins that then move the cell in the direction of cycling
• The Cdk effect on the cell cycle is a common mechanism in eukaryotic cells
• studies in sea urchin eggs uncovered this protein for the first time called the maturation promoting factor (MPF) while a mutant yeast that lacked Cdk was found, which stalled at the G₁→S boundary. These two proteins were similar in structure and function
• other Cdks have been found in other organisms, including humans
• Cyclin is a protein that interacts with Cdk
• binding of Cyclin to Cdk exposes the active site of the kinase and the cyclin-Cdk complex now acts as a protein kinase that triggers transition from G1→S. The cyclin then breaks down and the Cdk becomes inactive.
• Several different cyclins exist, which, when bound to Cdk, phosphorylate different target proteins
1. Cyclin D-Cdk4 acts during the middle of G₁. This is the restriction point in G₁, beyond which the rest of the cell cycle is inevitable
2. Cyclin E-Cdk2 acts at the boundary of G₁ to S to initiate DNA replication
3. Cyclin A-Cdk2 acts during S and also stimulates DNA replication
4. Cyclin B-Cdk1 acts at the G₂-to-M boundary, initiating mitosis
• Cyclin-Cdk complexes act as checkpoints. When functioning properly, they allow or prevent the passage to the next cell cycle stage, depending on the extra- and intracellular conditions. An example is the effect of p21 on the G₁-to-S phase transition:
• if DNA is damaged by UV radiation, p21 is synthesized (a protein of 21,000 daltons) and it binds to the two different types of G₁ Cdk molecules, preventing their activation until damaged DNA is repaired. The p21 is then degraded, allowing the cell cycle to proceed
• Some targets for cyclin-Cdk complexes include proteins that condense chromosomes and others that cause fragmentation of the nuclear envelope
• Cyclin-Cdk defects have been found in some cancer cells
• a breast cancer with too much cyclin D has been found
• the protein p53, which inhibits activation of Cdk, is found defective in half of all human cancers.

Growth factors stimulate the cells to divide

• Cyclin-Cdk complexes provide internal control for cell cycle decisions, i.e. since the cells in multicellular organisms must divide only when appropriate, they must therefore respond to external signals, controls called growth factors
• Some cells respond to growth factors provided by other cells, for example:
• platelets release platelet-derived growth factor (PDGF) required for the division of fibroblasts, which diffuses to the surface of cells to stimulate wound healing by binding to tyrosine kinase receptors on surface of cells thus triggering a signal transduction pathway
• interleukins are released from one type of blood cell to stimulate division of another type resulting in body immune system defenses
• the cells of the kidney make erythropoietin, which stimulates bone marrow cells to divide and differentiate into red blood cells
• cancer cells cycle inappropriately because they either make their own growth factors or no longer require them to start cycling

Regulation of the Cell Cycle

• Cell cycle is driven by specific chemical signals in the cytoplasm
• Cell cycle control system triggers and coordinates key events in the cell cycle
• Cell cycle checkpoints act as stop and go signals → 3 major checkpoints found in G₁, G₂, and M phases
• G₁ is critical checkpoint. If cells make it past G₁, then the entire cell cycle is completed
• non-dividing cells are in G₀ state and can get back into the cell cycle upon appropriate stimulation
• Protein kinases are activated by cyclin proteins → their activity is correlated with concentration of specific cyclin (hence the term cyclin dependent kinase or "Cdk")

Cyclin level rises during the interphase

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At  G₂ enough active M-phase Promoting Factor (MPF), i.e. the cyclin-Cdk complex is present to promote mitosis

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A number of phosphorylation events carried out by cyclin-CdK complex cause nuclear envelope to fragment and activate other enzymes

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Cyclin is subsequently broken down by proteolytic cleavage (MPF becomes inactive) and Cdk is then recycled

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Proteolysis of the complex also drives M-phase past anaphase by breaking down proteins that hold sister chromatids together

Internal and external cues regulate the cell cycle

• internal signal delays start of anaphase (separation of chromosomes) until all kinetochores are attached to spindle fibers
• Anaphase promoting complex (APC) is kept in inactive state by proteins associated with kinetochores
• Signal ceases when all kinetochores are attached
• Density dependent inhibition describes phenomenon whereby cells stop growing after reaching a certain density. Growth is limited by availability of growth factor

Cancer cells have escaped cell cycle controls

• cancer cells do not exhibit density dependent inhibition as they do not stop growing when growth factor is depleted
• cancer cells stop at random points in cell cycle (not checkpoints)
• some cancer cell lines are immortal and can divide indefinitely given the right ingredients, e.g. HeLa cells
• p53 gene mutations in tumor suppressor genes (e.g. p53) result in cancer. On the other hand, a functional p53 aids cell in checkpoint control at G₁ and G₂ phases