3.5 Cell Growth and Division

The cell cycle governs how cells grow and divide. It ensures that each new cell receives an accurate copy of the organism's DNA, which is essential for tissue growth, repair, and maintenance. This section covers the stages of the cell cycle, how the cell regulates division, and what happens when that regulation fails.

Cell Cycle and Mitosis

Stages of the Cell Cycle

The cell cycle has two major parts: interphase (where the cell prepares for division) and the mitotic phase (where the nucleus and cytoplasm actually divide).

Interphase takes up the majority of the cell cycle and includes three sub-phases:

• G1 phase (Gap 1): The cell grows in size, carries out normal metabolic functions, and prepares for DNA synthesis. Centrosome duplication also begins here.
• S phase (Synthesis): DNA replication occurs. Each chromosome is duplicated, producing two identical sister chromatids joined at the centromere.
• G2 phase (Gap 2): The cell continues to grow and synthesizes proteins needed for mitosis, such as tubulin for spindle fibers.

Mitosis is the division of the nucleus into two genetically identical nuclei. It has four classical stages: prophase, metaphase, anaphase, and telophase. (Prometaphase is sometimes listed as a distinct fifth stage between prophase and metaphase.)

Cytokinesis divides the cytoplasm after the nucleus has split. In animal cells, a cleavage furrow pinches the cell in two. In plant cells, a cell plate forms at the midline and expands outward.

The end result: two genetically identical daughter cells.

Regulation of the Cell Cycle

Cells don't just barrel through the cell cycle on autopilot. A system of proteins and checkpoints keeps everything on track.

Cyclins and Cyclin-Dependent Kinases (CDKs)

Cyclins are regulatory proteins whose levels rise and fall at specific points in the cell cycle. CDKs are enzymes that are always present in the cell but only become active when bound to a cyclin. Together, specific cyclin-CDK complexes drive the cell from one phase to the next:

• Cyclin D with CDK4/6 promotes progression through G1
• Cyclin E with CDK2 triggers the G1/S transition
• Cyclin A with CDK2 drives S phase
• Cyclin B with CDK1 pushes the cell into mitosis (M phase)

The key idea: cyclin levels oscillate throughout the cycle while CDK levels stay relatively constant. It's the changing availability of cyclins that acts as the timing mechanism.

Checkpoints

Checkpoints are surveillance mechanisms that pause the cell cycle if something is wrong.

• G1 checkpoint (restriction point): Checks whether the cell is large enough, has adequate nutrients, and is receiving appropriate growth factor signals. Once a cell passes this point, it's committed to dividing.
• G2/M checkpoint: Verifies that DNA replication is complete and checks for DNA damage before the cell enters mitosis.
• Spindle assembly checkpoint (SAC): Operates during metaphase. Proteins like Mad2 and BubR1 prevent the onset of anaphase until every chromosome is properly attached to spindle fibers from both poles. This prevents unequal distribution of chromosomes.

Tumor Suppressors

Two major tumor suppressor proteins act as brakes on the cell cycle:

• p53 responds to DNA damage by halting the cell cycle to allow repair. If the damage is too severe, p53 triggers apoptosis (programmed cell death). It's often called the "guardian of the genome" because it prevents cells with damaged DNA from dividing.
• Retinoblastoma protein (pRb) controls the G1/S transition. In its unphosphorylated state, pRb binds to E2F transcription factors and blocks them from activating genes needed for S phase. When cyclin-CDK complexes phosphorylate pRb, it releases E2F, and the cell proceeds into S phase.

Cell Growth Control and Differentiation

Beyond the internal checkpoints, external signals also influence whether a cell divides.

• Contact inhibition: Normal cells stop dividing when they form a single layer (monolayer) and physically contact neighboring cells. Cancer cells typically lose this property.
• Density-dependent inhibition: Cell division slows or stops when the local cell population reaches a certain density, partly due to depletion of growth factors in the surrounding environment.
• Cell differentiation: As organisms develop, most cells specialize into distinct cell types (muscle, nerve, epithelial, etc.) with specific functions. Differentiated cells often exit the cell cycle and enter a quiescent state called G0.
• Apoptosis: A tightly regulated form of programmed cell death that removes damaged, infected, or unnecessary cells without triggering inflammation.
• Cell cycle arrest: Various stressors (DNA damage, nutrient deprivation, telomere shortening) can temporarily or permanently halt cell division.

Cell Cycle Dysregulation Consequences

When the regulatory mechanisms described above fail, the consequences can be severe.

Cancer arises from uncontrolled cell division caused by mutations in cell cycle regulatory genes. Two categories of genes are typically involved:

• Oncogenes are mutated versions of normal genes (proto-oncogenes) that promote cell proliferation. For example, overexpression of cyclin D or constitutive activation of CDK4 can push cells through G1 without proper checks.
• Tumor suppressor gene inactivation: Loss of p53 or pRb function removes critical brakes on the cell cycle, leading to genomic instability and accumulation of further mutations.

Neurodegenerative disorders can involve abnormal cell cycle re-entry in post-mitotic neurons (neurons that should never divide again). This aberrant re-entry leads to neuronal death rather than successful division, and has been associated with Alzheimer's disease (linked to amyloid beta accumulation) and Parkinson's disease (linked to alpha-synuclein aggregation).

Developmental disorders can result from cell cycle abnormalities during embryonic development. Examples include holoprosencephaly (a brain development defect) and conditions associated with trisomy 13, which can cause severe birth defects or embryonic lethality.

Aging is associated with cellular senescence, a state of permanent cell cycle arrest triggered by accumulated stress or damage. Senescent cells secrete inflammatory molecules (called the senescence-associated secretory phenotype, or SASP), which contributes to chronic inflammation and age-related tissue dysfunction over time.

Events of Mitosis and Cytokinesis

Here's a step-by-step breakdown of what happens during each stage:

1. Prophase

   • Chromatin condenses into tightly coiled chromosomes that become visible under a light microscope.
   • Centrosomes migrate to opposite poles of the cell and begin forming the mitotic spindle.
   • The nuclear envelope breaks down into vesicles, releasing the chromosomes into the cytoplasm.

2. Prometaphase

   • Kinetochores (protein structures) assemble on the centromere of each chromosome, serving as attachment points for spindle microtubules.
   • Spindle microtubules extend outward and capture kinetochores through a search-and-capture mechanism.
   • Chromosomes begin moving toward the center of the cell in a process called congression.

3. Metaphase

   • All chromosomes align along the metaphase plate (the equatorial plane of the cell).
   • Spindle fibers from opposite poles attach to the kinetochores of sister chromatids, creating tension that confirms proper attachment.
   • The spindle assembly checkpoint (SAC) verifies that every chromosome is correctly attached before the cell proceeds.

4. Anaphase

   • The enzyme separase cleaves cohesin proteins that hold sister chromatids together, allowing them to separate.
   • Anaphase A: Spindle fibers shorten, pulling the now-individual chromatids toward opposite poles.
   • Anaphase B: The poles themselves move farther apart as motor proteins push on overlapping microtubules between them.

5. Telophase

   • Chromatids (now called chromosomes) arrive at opposite poles and begin to decondense back into loosely coiled chromatin.
   • A new nuclear envelope re-forms around each set of chromosomes, assembled from endoplasmic reticulum membrane vesicles.
   • The nucleolus reappears in each forming nucleus.
   • Spindle fibers disassemble.

6. Cytokinesis

   • In animal cells, a contractile ring made of actin and myosin filaments assembles at the cell equator. This ring contracts, forming a cleavage furrow that deepens until it pinches the cell into two separate daughter cells.
   • In plant cells, vesicles from the Golgi apparatus fuse at the midline to form a cell plate, which expands outward until it reaches the existing cell wall, dividing the cytoplasm.
   • The result in both cases: two genetically identical daughter cells, each with a complete copy of the genome.