1. Reproduction of Cells and the Cell Cycle
Chapter 12

2. Functions of Cell Division (mitosis)
Multicellular organisms: growth, development, and repair.
Cell division allows organisms to grow while maintaining surface area-to-volume ratio; adds more cells.
Also provides more cells that can become specialized, as well as replacing damaged or dead cells.
Unicellular organisms: reproduction.
Cell division, also called binary fission, is a form of asexual reproduction.
New cells will be clones of the original cell.

4. Chromosomes
Eukaryotic cells contain genes (sequences of DNA) which are organized into multiple chromosomes.
Chromosomes -- Threadlike structures composed of DNA and proteins.
• Each species has a characteristic chromosome number; Human somatic (body) cells have 46; diploid number.
• Gametes (sperm and egg) contain half the number of chromosomes of somatic cells; Human gametes have 23; haploid number.
Chromatin -- a long, thin fiber that is folded and coiled to form the chromosome.

5. Chromosomes (cont)
Before division, chromosomes are duplicated, forming an X-shaped structure made up of two identical strands of DNA (sister chromatids) joined at a specialized region called the centromere or kinetochore.
Mitosis -- (Mitos = thread) Division of the cell’s nucleus when duplicated chromosomes are evenly distributed into two daughter nuclei, ensuring that two new daughter cells will be genetically identical to the parent cell.
Cytokinesis – Division of the cell’s cytoplasm that may follow mitosis; forms two separate daughter cells, each containing a single nucleus.

7. The Cell Cycle
Cell cycle -- Sequence of events including mitosis, cytokinesis, cell growth, and preparation for the next division.
Some cells divide each hour, others take more than 24 hours; Nerve and muscle cells never or rarely divide once they are formed.
Cell cycle alternates between M phase (cell division) and Interphase.
Interphase -- includes most of a cell's growth and metabolic activities; about 90% of the cell cycle.
1. G1 phase – cell growth. (G stands for "gap".)
2. S phase -- DNA is made as chromosomes are duplicated. (S stands for "synthesis".)
3. G2 phase – final prep for division and cell growth.
M phase -- shortest part of the cell cycle; cell divides.
1. Mitosis -- division of the nucleus.
2. Cytokinesis -- division of the cytoplasm (cytosol and organelles).

9. Stages of Mitosis
Mitosis is usually divided into five stages: prophase, prometaphase, metaphase, anaphase and telophase.
IPPMATC can be used to remember all phases of the cell cycle.
[I] Characteristics of a late interphase cell:
Well-defined nucleus bounded by a nuclear envelope.
One or more nucleoli.
Two centrosomes adjacent to the nucleus (area from which microtubules originate).
In animals, a pair of centrioles in each centrosome (structures made of microtubules which assist in assembly of the spindle or aster).
Chromatin (loosely packed, duplicated chromosomes that cannot be distinguished individually).

10. Stages of Mitosis (cont)
[P] Prophase:
Nucleoli disappear.
Chromatin fibers condense into observable chromosomes.
Mitotic spindle forms, composed of microtubules between the two centrosomes or microtubule-organizing centers.
Centrosomes move apart.
[P] Prometaphase:
Nuclear envelope disintegrates so spindle can interact with chromosomes.
Spindle fibers (bundles of microtubules) extend from each pole toward the cell's equator; some attach to chromosomes.
Kinetochore microtubules attach to the kinetochores from the centriole.
Nonkinetochore (or spindle) microtubules radiate from centriole to centriole at opposite pole.

14. Stages of Mitosis (cont)
[M] Metaphase:
Centrosomes are positioned at opposite poles of the cell.
Chromosomes move to the metaphase plate, the plane between the poles.
Centromeres of all chromosomes are aligned on the metaphase plate, connected to spindle fibers.
[A] Anaphase:
Centromeres divide as sister chromatids pull apart into separate chromosomes and move towards opposite poles of the cell.
Kinetochore microtubules shorten at the kinetochore end as chromosomes approach the poles.
The poles of the cell also move farther apart, elongating the cell.

16. Stages of Mitosis (end)
[T] Telophase:
Daughter nuclei begin to form at the two poles.
Nuclear envelopes form around the chromosomes.
Nucleoli reassemble.
Chromatin of each chromosome uncoils and the chromosomes become less distinct.
Cytokinesis begins.
[C] Cytokinesis:
Cytoplasmic division begins in telophase.
In animal cells, cytokinesis occurs as cleavage.
• Cleavage furrow forms on the cell surface near the old metaphase plate.
• Contractile ring of actin microfilaments forms on the cytoplasmic side and contracts until it pinches the parent cell in two.
In plant cells, cytokinesis occurs by cell plate formation across the parent cell's midline (old metaphase plate).
• Golgi vesicles move to the old metaphase plate where they fuse into a cell plate, then finally fuse with the existing plasma membrane.
• A new cell wall forms as cellulose is deposited between the two membranes of the cell plate.

19. Regulation of the Cell Cycle
External and internal cues control cell division.
1. Cell membrane receptors (nutrients, pH, chemical growth factors).
2. Cell density -- Crowding inhibits cell division (density-dependent inhibition).
3. G1 phase of the cell cycle -- If a cell is going to divide, it progresses beyond the R (restriction) point then proceeds with DNA synthesis.
If the cell is not going to divide, it may exit from the cell cycle at the restriction point and switch to a nondividing state called the G0 phase.
4. Cell size -- cytoplasmic volume is the most important indicator of whether a cell will pass the restriction point.

20. Regulation of the Cell Cycle (cont)
5. Regulatory proteins – Cyclin and protein kinases.
Cyclin is produced at a uniform rate throughout the cell cycle; it accumulates during interphase, then triggers mitosis.
Protein kinases are often controlled by cyclins.
An example of a cyclin-dependent kinase is MPF (maturation promoting factor).
• Active MPF phosphorylates chromatin proteins, causing chromosomes to condense during prophase.
• During prometaphase, the nuclear envelope breaks down when some of its membrane proteins are phosphorylated.
Near the end of mitosis, cyclin is destroyed by an enzyme that is activated by MPF.
The destruction of cyclin causes the decline in active MPF at the end of mitosis.
(ANOTHER EXAMPLE OF FEEDBACK CONTROL)

21. Cancer cells escape from the controls on cell division
Cancer cells divide excessively and ignore density-dependent inhibition.
Cancer cells will divide indefinitely as long as nutrients are available. Normal mammalian cells divide about 20 to 50 times before they stop; there is a culture of cancer cells that have been dividing in a lab since 1951.
The immune system normally destroys abnormal cells that have converted from normal to cancer cells.
If not destroyed, abnormal cells form a tumor.
• In benign tumors, the cells remain at the original site.
• A tumor is malignant (cancer) if the cells have the ability to damage tissue and to spread to other parts of the body.
Detached cancer cells may spread into other tissues surrounding the original tumor and may even enter the blood and lymph vessels of the circulatory system (metastasis).

23. Tumor Suppressor Genes
The protein products of tumor suppressor genes can directly or indirectly prevent cell division or lead to cell death.
Tumor suppressors can be likened to the brake system in a car.
Loss of function of tumor suppressors leads to abnormal cellular behavior.
Car Analogy

24. Key Tumor Suppressor Genes
A transcription factor that regulates genes controlling cell division and cell death.
Important in the cellular response to DNA damage.
Aids in decision between repair and induction of cell death. Rb
Functions by altering transcription factor activity.
Contributes to the control of cellular division by acting as an inhibitor.
APC
The APC protein binds and stimulates the degradation of a transcription factor.
Absence of functional APC protein leads to increased cell division. (Animation)
BRCA
BRCA proteins have multiple functions including repairing DNA damage and regulation of gene expression.
Non-functional BRCA leads to compromised DNA repair and gene regulation. (Animation)

25. Cancer Treatment
New cancer drugs target the cell cycle by inhibiting division internally or externally.
Taxol and spindle formation
Herceptin and membrane receptors and animation