BIS 1A Handout 12 - The Cell Cycle

The Key Roles of Cell Division

The continuity of life is based on the reproduction of cells, or cell division.

The division of a unicellular organism reproduces an entire organism, increasing the population.

In a multicellular organism, cell division functions to repair and renew cells that die from normal use or accidents.

Cell division results in genetically identical daughter cells

Cell division requires the distribution of identical genetic material-DNA-to two daughter cells.

A dividing cell duplicates its DNA, allocates the two copies to opposite ends of the cell, and then splits into two daughter cells.

A cell's genetic information, packaged as DNA, is called its genome.

In prokaryotes, the genome is often a single long DNA molecule.

In eukaryotes, the genome consists of several DNA molecules.

A human cell must duplicate about 2 m of DNA and separate the two copies such that each daughter cell ends up with a complete genome. An average nucleus is 5 micrometres in diameter.

DNA molecules are packaged into chromosomes.

Eukaryotic chromosomes are made of chromatin, a complex of DNA and associated protein.

When a cell is not dividing, each chromosome is in the form of a long, thin chromatin fiber.

Before cell division, chromatin condenses, coiling and folding to make a smaller package.

Each duplicated chromosome consists of two sister chromatids, which contain identical copies of the chromosome's DNA.

The chromatids are initially attached by adhesive proteins along their lengths.

As the chromosomes condense, the region where the chromatids connect shrinks to a narrow area, the centromere.

Later in cell division, the sister chromatids are pulled apart and repackaged into two new nuclei at opposite ends of the parent cell.

Mitosis, the formation of the two daughter nuclei, is usually followed by division of the cytoplasm, cytokinesis.

These processes start with one cell and produce two cells that are genetically identical to the original parent cell.

The mitotic phase alternates with interphase in the cell cycle

The mitotic (M) phase of the cell cycle alternates with the much longer interphase.

The M phase includes mitosis and cytokinesis.

Interphase accounts for 90% of the cell cycle time.

During interphase, the cell grows by producing proteins and cytoplasmic organelles, copies its chromosomes, and prepares for cell division.

Interphase has three subphases: the G1 phase ("first gap"), the S phase ("synthesis"), and the G2 phase ("second gap"). Chromosomes are duplicated only during the S phase.

A typical human cell might divide once every 24 hours.

Of this time, the M phase would last less than an hour, while the S phase might take 10-12 hours, or half the cycle.

The rest of the time would be divided between the G1 (variable) and G2 phases.

For convenience, mitosis is usually broken into five subphases: prophase, prometaphase, metaphase, anaphase, and telophase.

In late interphase, the chromosomes have been duplicated (S phase finished) but not condensed.

A nuclear membrane bounds the nucleus, which contains one or more nucleoli.

The centrosome has replicated to form two centrosomes.

In animal cells, each centrosome features two centrioles.

In prophase, the chromosomes are tightly coiled, with sister chromatids joined together.

The nucleoli disappear.

The mitotic spindle begins to form.

It is composed of centrosomes and the microtubules that extend from them.

During prometaphase, the nuclear envelope fragments, and microtubules from the spindle interact with the condensed chromosomes.

Each of the two chromatids of a chromosome has a kinetochore, a specialized protein structure located at the centromere.

Kinetochore microtubules from each pole attach to one of two kinetochores.

The spindle fibers push the sister chromatids until they are all arranged at the metaphase plate, an imaginary plane equidistant from the poles, defining metaphase.

At anaphase, the centromeres divide, separating the sister chromatids.

Each is now pulled toward the pole to which it is attached by spindle fibers.

By the end, the two poles have equivalent collections of chromosomes.

At telophase, daughter nuclei begin to form at the two poles.

Nuclear envelopes arise from the fragments of the parent cell's nuclear envelope and other portions of the endomembrane system.

The chromosomes become less tightly coiled.

Cytokinesis, division of the cytoplasm, is usually well underway by late telophase.

In animal cells, cytokinesis involves the formation of a cleavage furrow, which pinches the cell in two.

In plant cells, vesicles derived from the Golgi apparatus produce a cell plate at the middle of the cell.

The mitotic spindle distributes chromosomes to daughter cells: a closer look.

As the spindle assembles during prophase, the elements come from partial disassembly of the cytoskeleton.

The spindle includes the centrosomes, the spindle microtubules, and the asters.

During prometaphase, some spindle microtubules (called kinetochore microtubules) attach to the kinetochores. The chromosome moves toward the pole from which those microtubules come.

When microtubules attach to the other pole, this movement stops and a tug-of-war ensues.

Eventually, the chromosome settles midway between the two poles of the cell, on the metaphase plate.

Nonkinetochore microtubules from opposite poles overlap and interact with each other.

Anaphase commences when the proteins holding the sister chromatids together are inactivated.

Experimental evidence supports the hypothesis that motor proteins on the kinetochore "walk" the attached chromosome along the microtubule toward the nearest pole.

Meanwhile, the excess microtubule sections depolymerize at their kinetochore ends.

Nonkinetochore microtubules are responsible for lengthening the cell along the axis defined by the poles.

These microtubules interdigitate and overlap across the metaphase plate.

During anaphase, the area of overlap is reduced as motor proteins attached to the microtubules walk them away from one another, using energy from ATP.

Cytokinesis divides the cytoplasm: a closer look.

In animal cells, cytokinesis occurs by a process called cleavage.

The first sign of cleavage is the appearance of a cleavage furrow in the cell surface near the old metaphase plate.

On the cytoplasmic side of the cleavage furrow is a contractile ring of actin microfilaments associated with molecules of the motor protein myosin.

Contraction of the ring pinches the cell in two.

Cytokinesis in plants, which have cell walls, involves a completely different mechanism.

During telophase, vesicles from the Golgi coalesce at the metaphase plate, forming a cell plate.

The plate enlarges until its membranes fuse with the plasma membrane at the perimeter.

The contents of the vesicles form new cell wall material between the daughter cells.

Mitosis in eukaryotes may have evolved from binary fission in bacteria.

Prokaryotes reproduce by binary fission, not mitosis.

Most bacterial genes are located on a single bacterial chromosome that consists of a circular DNA molecule and associated proteins.

In binary fission, chromosome replication begins at one point in the circular chromosome, the origin of replication site, producing two origins.

As the chromosome continues to replicate, one origin moves toward each end of the cell.

While the chromosome is replicating, the cell elongates.

When replication is complete, its plasma membrane grows inward to divide the parent cell into two daughter cells, each with a complete genome.

How did mitosis evolve?

There is evidence that mitosis had its origins in bacterial binary fission.

Some of the proteins involved in binary fission are related to eukaryotic proteins.

Two of these are related to eukaryotic tubulin and actin proteins.

As eukaryotes evolved, the ancestral process of binary fission gave rise to mitosis.

Possible intermediate evolutionary steps are seen in the division of two types of unicellular algae.

In dinoflagellates, replicated chromosomes are attached to the nuclear envelope.

In diatoms, the spindle develops within the nucleus.

The cell cycle is regulated by a molecular control system

The timing and rates of cell division in different parts of an animal or plant are crucial for normal growth, development, and maintenance.

The frequency of cell division varies with cell type.

Some human cells divide frequently throughout life (skin cells).

Mature nerve and muscle cells do not appear to divide at all after maturity.

Cytoplasmic signals drive the cell cycle.

The cell cycle appears to be driven by specific chemical signals present in the cytoplasm.

The sequential events of the cell cycle are directed by a distinct cell cycle control system.

The control cycle has a built-in clock, but it is also regulated by external adjustments and internal controls.

A checkpoint in the cell cycle is a critical control point where stop and go-ahead signals regulate the cycle.

Animal cells generally have built-in stop signals that halt the cell cycle at checkpoints until overridden by go-ahead signals.

Three major checkpoints are found in the G1, G2, and M phases.

For many cells, the G1 checkpoint, the "restriction point" in mammalian cells, is the most important.

If the cell receives a go-ahead signal at the G1 checkpoint, it usually completes the cell cycle and divides.

If it does not receive a go-ahead signal, the cell exits the cycle and switches to a nondividing state, the G0 phase. Most cells in the human body are in this phase.

Rhythmic fluctuations in protein kinase activity controls the events of the cell cycle.

These kinases are present in constant amounts but require attachment of a second protein, a cyclin, to become activated.

Because of the requirement for binding of a cyclin, the kinases are called cyclin-dependent kinases, or Cdks.

Cyclin levels rise sharply throughout interphase, and then fall abruptly during mitosis.

Peaks in the activity of one cyclin-Cdk complex, MPF, correspond to peaks in cyclin concentration.

MPF ("maturation-promoting factor" or "M-phase-promoting-factor") triggers the cell's passage past the G2 checkpoint to the M phase.

It also triggers the breakdown of cyclin, dropping cyclin and MPF levels during mitosis and inactivating MPF.

At least three Cdk proteins and several cyclins regulate the key G1 checkpoint.

Similar mechanisms are also involved in driving the cell cycle past the M phase checkpoint.

Internal and external cues help regulate the cell cycle.

The M phase checkpoint ensures that all the chromosomes are properly attached to the spindle at the metaphase plate before anaphase.

This ensures that daughter cells do not end up with missing or extra chromosomes.

A signal to delay anaphase originates at kinetochores that have not yet attached to spindle microtubules.

A variety of external chemical and physical factors can influence cell division.

For example, cells fail to divide if an essential nutrient is left out of the culture medium.

Particularly important for mammalian cells are growth factors, proteins released by one group of cells that stimulate other cells to divide.

For example, platelet-derived growth factors (PDGF), produced by platelet blood cells, bind to tyrosine-kinase receptors of fibroblasts, a type of connective tissue cell.

This triggers a signal-transduction pathway that allows cells to pass the G1 checkpoint and divide.

In a living organism, platelets release PDGF in the vicinity of an injury.

The resulting proliferation of fibroblasts helps heal the wound.

At least 50 different growth factors can trigger specific cells to divide.

The effect of an external physical factor on cell division can be seen in density-dependent inhibition of cell division.

Cultured cells normally divide until they form a single layer on the inner surface of the culture container.

Most animal cells also exhibit anchorage dependence for cell division.

To divide, they must be anchored to a substratum, typically the extracellular matrix of a tissue.

Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence.

Cancer cells have escaped from cell cycle controls.

Cancer cells divide excessively and invade other tissues because they are free of the body's control mechanisms.

Cancer cells do not stop dividing when growth factors are depleted.

This is either because a cancer cell manufactures its own growth factors, has an abnormality in the signaling pathway, or has an abnormal cell cycle control system.

Cancer cells may divide indefinitely if they have a continual supply of nutrients.

In contrast, nearly all mammalian cells divide 20 to 50 times under culture conditions before they stop, age, and die.

Cancer cells may be "immortal."

HeLa cells from a tumor removed from a woman (Henrietta Lacks) in 1951 are still reproducing in culture.

The abnormal behavior of cancer cells begins when a single cell in a tissue undergoes a transformation that converts it from a normal cell to a cancer cell.

Normally, the immune system recognizes and destroys transformed cells.

However, cells that evade destruction proliferate to form a tumor, a mass of abnormal cells.

If the abnormal cells remain at the originating site, the lump is called a benign tumor.

Most do not cause serious problems and can be fully removed by surgery.

In a malignant tumor, the cells become invasive enough to impair the functions of one or more organs.

In addition to chromosomal and metabolic abnormalities, cancer cells often lose attachment to nearby cells, are carried to other tissues, and start more tumors in an event called metastasis.

Treatments for metastasizing cancers include X-irradiation and chemotherapy with toxic drugs.

These treatments target actively dividing cells.

For example, Taxol prevents cells from proceeding past metaphase.

The side effects of chemotherapy are due to the drug's effects on normal cells.

Researchers are beginning to understand how a normal cell is transformed into a cancer cell.

The causes are diverse, but cellular transformation always involves the alteration of genes that influence the cell cycle control system.