The Cell Cycle

Chapter 12 & part of chapter 11

All cells come from pre-existing cells

• One characteristic that distinguishes living from non-living is the ability to reproduce

• Cellular reproduction allows the continuity of life, growth and repair

• Cellular reproduction can be asexual or vegetative, or sexual

8-cell human embryo

Sperm that did not make it in

Asexual / Vegetative Reproduction

• Does not involve exchange of genetic material• Daughter cell is a clone of parent cell (genetically

identical)• Performed by:

- bacteria (binary fission), - protists- yeast (budding)- certain plants (sprouting of potato eyes)

Asexual / Vegetative Reproduction

Plant cuttings will sprout roots, as will a potato, which is a tuber – a modified, underground stem.

Asexual Reproduction – Binary Fission

The prokaryotic chromosome is bound to plasma membrane, in the nucleoid region of the cell. It remains bound, even after it is duplicated, as the cell begins to elongate. This causes the parent and daughter chromosomes to separate – eventually the cell splits into two identical cells (Clones)

Asexual reproduction - budding

Hydra

Yeast

Mold

Genetically identical clones

Asexual is good – sexual is better!

• Although asexual reproduction is energy and time efficient, sexual reproduction allows genetic variations that may increase the species chances of survival

• Most organisms that normally reproduce asexually, can also reproduce sexually, i.e they can create offspring that are genetically different (not clones)

• Sexual reproduction for these organisms usually follows environmental stress such as a lack of food and other resources

Asexual reproduction in eukaryotes is known as MITOSIS

• Mitosis is the division of the nucleus and its contents

• Mitosis is followed by cytokinesis – the division of the cytoplasm

All somatic cells reproduce mitoticallyAll somatic cells reproduce mitotically

• Somatic cells are Somatic cells are allall the cells of the body, the cells of the body, exceptexcept the gametes (egg and sperm) the gametes (egg and sperm)

• Skin cells, liver cells, cells that line the G.I. Skin cells, liver cells, cells that line the G.I. tract, etc. are constantly dividing, to tract, etc. are constantly dividing, to replace dead cellsreplace dead cells

• Other cells such as neurons, adipose Other cells such as neurons, adipose cells, muscle cells, etc. never or rarely cells, muscle cells, etc. never or rarely dividedivide

The Cell CycleThe Cell Cycle• A A typicaltypical human cell undergoes a division about every human cell undergoes a division about every

24 hours (there are many exceptions!)24 hours (there are many exceptions!)

• The cell cycle is basically an alternation of 2 major The cell cycle is basically an alternation of 2 major phases – Mitosis and Interphasephases – Mitosis and Interphase

• Interphase is the phase in which the cell spends 23 of Interphase is the phase in which the cell spends 23 of the 24 hours – the cell grows, carries out its the 24 hours – the cell grows, carries out its “housekeeping duties” and its specialized activities“housekeeping duties” and its specialized activities

• Mitosis takes about 1 hourMitosis takes about 1 hour

The Cell Cycle, cont’d.

Interphase can be broken down into 3 distinct sub-phases:– G1 (Known as gap 1)– S (for synthesis of DNA)– G2 (gap 2)

Cells that do not divide are considered to be in a phase called G0 – where they carry on normal housekeeping and do not prepare to divide

The Cell Cycle

Phases of Interphase Phases of Interphase • G1 phase:G1 phase: The period prior to the synthesis of DNA. The period prior to the synthesis of DNA.

In this phase, the cell prepares for cell divisionIn this phase, the cell prepares for cell division- proteins are synthesized- proteins are synthesized- the cell increases in mass - the cell increases in mass

• S phase: S phase: The period after G1, where all genetic The period after G1, where all genetic material (DNA) is synthesizedmaterial (DNA) is synthesized

• G2 phase:G2 phase: The period after DNA synthesis has The period after DNA synthesis has occurred but prior to the start of mitosis. occurred but prior to the start of mitosis. - cell continues to increase in size- cell continues to increase in size- centrosome divides into 2- centrosome divides into 2- In animal cells, each centrosome has 2 centrioles- In animal cells, each centrosome has 2 centrioles

How DNA Packs into a Metaphase Chromosome

ChromosomesA human Karyotype

All somatic cells are Diploid (2n)• The cells have 2 versions of every DNA strand or chromosome

• The 2 versions are called homologous chromosomes

•One homologue comes from the sperm and the other from the egg

•Human somatic cells have 46 chromosomes – or 23 homologous chromosome pairs

DNA (chromosome) replication

• The cell has to replicate (duplicate) all its DNA

• The duplicated DNA is then organized into distinct bundles called chromosomes – the duplicates are connected to each other at the centromere

• Each duplicated DNA strand is called a sister chromatid

• Human cells still have 46 chromosomes, and 23 homologous pairs, but 92 sister chromatids

DNA Replication

(p-arm)

(q-arm)

Duplicated Chromosome

What is the centromere?

• A centromere is a region of DNA typically found near the middle of a chromosome where two sister chromatids come in contact.

• The DNA in the centromere region typically contains tandem repetitive sequences, often called "satellite DNA" - it is considered “junk” DNA – as it doesn’t code for RNA

• During mitotic division, a transient structure called kinetochore is formed on top of the centromeres. The kinetochores are the sites where the spindle fibers attach.

The duplicated chromosome

The mitotic spindle at Metaphase

(Animal Cells only)

(Animal Cells only)

Centriole and centrosome duplication

•Centrioles exist in pairs, in the centrosome region of animal cells•Centrioles have microtubules arranged in 9 triplets

Centrosomes and Centrioles• The centrosome is the microtubule-organizing center (MTOC) of animal

cells. It contains a pair of centrioles.

• During interphase of an animal cell, the centrioles and in the centrosome are duplicated (not clear how ).

• At first the replicated pairs of centrioles remain in the same centrosomes region. Eventually, in Prophase, the original centrosome divides in two.

• Now each new centrosome has a pair of centrioles.

• These new centers synthesize microtubules in star-shaped clusters known as asters.

• As the asters move to opposite poles of the cells, the microtubules, with the help of the centrioles, become organized into a spindle-shaped formation that spans the cell.

• These spindle fibers act as guides for the alignment of the chromosomes as they separate later during the process of cell division.

Centrioles/centrosome – Important or not?Centrioles/centrosome – Important or not?

• Though centrioles and the centrosome play a role in the mitosis of animal Though centrioles and the centrosome play a role in the mitosis of animal cells, plant and fungal cells are able to reproduce without them – they cells, plant and fungal cells are able to reproduce without them – they have some other MTOC organelles.have some other MTOC organelles.

• Researchers have, therefore, been very interested in determining exactly Researchers have, therefore, been very interested in determining exactly how important the organelles really are. how important the organelles really are.

• Studies have shown that certain animal cells, particularly female gametes Studies have shown that certain animal cells, particularly female gametes (oocytes), can successfully divide even when their centrioles are (oocytes), can successfully divide even when their centrioles are destroyed. destroyed.

• Some investigators have also found, however, that the absence of Some investigators have also found, however, that the absence of centrioles in animal cells is associated with an increased number of centrioles in animal cells is associated with an increased number of divisional errors and substantial delays in the mitotic process, especially divisional errors and substantial delays in the mitotic process, especially before chromosome segregation. before chromosome segregation.

• Consequently, it has been suggested that centrioles evolved as a Consequently, it has been suggested that centrioles evolved as a refinement of the cell, making mitosis a much more efficient and less refinement of the cell, making mitosis a much more efficient and less error-prone process.error-prone process.

Phases of Mitosis

• Prophase

• Prometaphase

• Metaphase

• Anaphase

• Telophase (followed immediately by cytokinesis)

Phases of Mitosis

Prophase Prometaphase

Anaphase

Metaphase

Telophase & beginning of cytokinesis

Completion of cytokinesis

G2 of Interphase

Prophase

1. Nuclear chromatin starts to become organized and condenses into thick strands that eventually become chromosomes observable in the optical microscope.

2. The nucleoli, primarily responsible for the production of ribosomal RNA, begin to disappear as the chromosomes condense.

3. The mitotic spindle, which is assembled by the centrosomes begins to appear along the periphery of the nuclear membrane. These are called asters or stars

4. Centrosomes begin to move apart

Prometaphase

• Nuclear membrane begins to fragment

• This allows spindle fibers to invade the nuclear space and interact with chromosomes

• Chromosomes are extremely dense and each sister chromatid has a protein complex at the centromere called a kinetochore

• Some microtubules (spindle fibers) attach to chromosome kinetochores

• Other microtubules (spindle fibers) interact with those from the opposite pole of the mitotic spindle

Metaphase

• Centrosomes are at opposite poles

• The chromosomes, attached to the kinetochore microtubules, begin to align in a single plane (known as the metaphase plate) midway between the spindle poles

• Each sister chromatid’s kinetochore is attached to a spindle fiber coming from opposite poles

Anaphase

• Sister chromatids pull apart and are now considered daughter chromosomes

• * Hypothesis - the motor proteins in the kinetochore move the chromosome along the microtubule toward the poles.

• Nonkinetochore microtubules lengthen, pushing the centrosomes further apart.

• At the end of anaphase, each group of chromosomes is clustered at opposite poles.

Telophase

• In animal cells, the cleavage furrow begins to form due to an actin ring (microfilaments)

• In plant cells there is no cleavage furrow – a cell plate forms (discussed later)

• Nuclear membrane begins to re-form

• The mitotic spindle begins to disassemble

• Chromosomes begin to return to chromatin state

• Nucleolus begins to reappear

Interphase

• Nucleus contains chromatin

• Only one set of centrioles (one centrosome)

• Fully formed nuclear membrane

• Fully formed nucleolus

Centrioles will replicate once the cell is ready to

divide again

What happens in the Kinetochore during

Anaphase?

1. Motor proteins called Dyenins “walk” along the microtubules, carrying the chromosomes toward the spindle poles.

2. The microtubules get disassembled as the chromosome moves toward the poles.

G2 - Interphase

Prophase

Metaphase

Anaphase

Telophase

Cytokinesis

PROPHASE

PROMETAPHASE

METAPHASE

ANAPHASE

TELOPHASE

Cytokinesis in Animal Cells

Contractile ring made of actin microfilaments, “pinches” the cell into two.

Cleavage Furrow

Cytokinesis in Plant Cells

Plant cells cannot be “pinched” into two new daughter cells, because of the cell wall.

The Golgi body secretes cell wall material packaged in transport vesicles that line up on the equator. These vesicles fuse to create a cell plate.

The cell plate divides the cell in two. The cell plate becomes the cell wall.

Cyclical changes in DNA of cell

Cell Cycle Checkpoints• If cell size inadequate

– G1 or G2 arrest

• If nutrient supply inadequate

– G1 arrest

• If an essential external stimulus is lacking– G1 arrest (at R)

• If the DNA is not replicated

– S arrest

• If DNA damage is detected

– G1 or G2 arrest

• If the spindle formation is improper, chromosome misalignment– M-phase arrest

RR

Cdks and cyclinsCyclin-dependent kinases (Cdks) are enzymes that are present in the cell cytoplasm at all times.

However, they are inactive unless they are bound by a specific partner-protein called a cyclin to form a Cdk-cyclin complex

The amount of cyclins in the cell changes – because they get degraded

A Cdk-cyclin complex will push the cell cycle forward.

Types of Cyclins and Cdks• There are many types of cyclins, but the 4 main ones

are:– Cyclin D (G1 cyclin)– Cyclin E (S-phase cyclin)– Cyclin A (S-phase and mitotic cyclin)– Cyclin B (mitotic cyclin)

• These are the 3 main cdks– Cdk4 (G1 Cdk)– Cdk2 (S-phase Cdk)– Cdk1 (mitotic Cdk)

• The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF) a.k.a maturation promoting factor

Rise and fall of cyclinsC

ycli

n C

on

cen

trat

ion

Mitosis

MPF (Mitosis Promotion Factor)

Cyclins are degraded by proteosomes, after they are tagged for degradation with a protein called ubiquitin. Ubiquitin is a big “TRASH” sign and proteasomes are protein shredders.

Protein ubiquitination and degradation

What is Cancer?Uncontrolled Cell division

Loss of cell cycle control and checkpoints

What does a cancerous cell look like?

•Large or multiple nuclei •Irregular shape

•Cells overlapping neighboring cells – loss of density-dependent or contact inhibition

•Loss of anchorage dependence

Tumors

• Benign - A spontaneous growth of tissue which forms an abnormal mass is called a tumor. A tumor that is noninvasive and noncancerous is referred to as a benign tumor.

• Malignant - A tumor that invades neighboring cells and is cancerous is referred to as a malignant tumor.

• Matastasis – Cancer that has spread to other tissues.

How we naturally fight cancer cells

• Tumor suppressor genes like p53– Can arrest the cell cycle– Can launch the apoptotic pathway, causing

the rogue cells to lyse

A mutation in the p53 gene can lead to cancer

• Immune cells (WBCs) such as NK cells can attack and lyse tumor cells– Some immune cells can signal the rogue cells

to launch the apoptotic pathways

Apoptosis vs. Necrosis

• Necrosis is traumatic cell death caused by injury. Necrosis of cells will lyse and damage neighboring cells by spilling all the intracellular contents. This causes inflammation of neighboring tissues and further trauma.

Apoptosis vs. Necrosis

• Apoptosis is programmed cell death, which prevents damage to neighboring cells by controlling how the affected cell dies

• During apoptosis, the cell's cytoskeleton is broken down, causing multiple bulges in the membrane. This is called blebbing.

• These blebs (a.k.a. apoptotic bodies) can separate from the cell, taking a portion of cytoplasm with them. Phagocytic cells eventually consume these fragments.

• Hence, apoptosis keeps damaged cellular contents from spilling out and damaging other cells.

Blebbing in Apoptosis

Necrotic cells

Necrotic cell with multiple lesions Apoptotic cell with blebbing

Signal Transduction Pathways • What are they?

– Signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another.

– A large number of proteins, enzymes and other molecules participate in a "signal cascade“

• What is the end result?– Either the activation or inhibition of a certain enzyme

in the cytoplasm– Either the expression or suppression of a particular

gene

Just a few examples of Signal Just a few examples of Signal Transduction PathwaysTransduction Pathways

• Cell Division signalsCell Division signals

• Apoptotic signalsApoptotic signals

• Insulin pathwaysInsulin pathways

Apoptotic Apoptotic Pathways Pathways

Insulin Signaling Pathway

The binding of insulin to its receptor on a cell starts a cascade of cellular events which finally leads to the uptake of glucose and the lowering of blood glucose levels.

THE END