Cell Growth and Cell Death

For cells to divide they must do what three things?

• GROW: make more molecules (proteins, lipids, etc.) termed (G) phase

• COPY THEIR GENETIC MATERIAL: via DNA synthesis termed (S) phase

• DIVIDE INTO TWO CELLS: via mitosis, termed the (M) phase

What is the cell cycle?

cycle of DNA synthesis and cell division (mitosis)

What is the definition of labile tissues, what are some examples?

• Divide continuously, proliferate throughout life

• Are derived from stem cells

• Examples: Surface epithelia of skin, epithelium of GI tract, cells in bone marrow, hematopoetic tissues

What is the definition of stable tissues, what are some examples?

• Quiescent cells; can divide with appropriate stimulus

• Examples: liver cells

What is the definition of permanent tissues what are some examples?

• Terminally differentiated cells, unable to undergo division

• Examples: neurons, skeletal and cardiac muscles, injury to brain/heart is irreversible (scarring)

Which cells in the body undergo the cell cycle on a regular basis and where are they located?

adult stem cells, in the bone marrow, skin and gut which require continual cell division to replenish cells

What are the four main phases (In order) of the cell cycle? Also include the fifth and final phase.

G1 —> S —> G2 —> M —> G0

What is the first phase of cell growth? What does this phase consist of?

• G1 Growth Phase

• Growth phase, cell prepares for DNA synthesis by making proteins needed for DNA replication

What is the second phase of cell growth? What does this phase consist of?

• S Phase

• DNA replication occurs

What is the third phase of cell growth? What does this phase consist of?

• G2 Growth Phase

• Cell prepares for mitosis, cell grows in size, replicates the organelles

What is the fourth phase of cell growth? What does this phase consist of?

• M Phase

• Mitosis phase, cell division, consisting of prophase, metaphase, anaphase, telophase

What is G0 phase of cell division? When do cells enter it?

• The 5th phase of the cell cycle, referring to cells that are no longer dividing

• Cells exit the cell cycle in G1 and enter G0 (A non-dividing state)

What is a “Temporary G0 Phase”, what is an example of cells that might undergo this?

• Some cells placed in G0 temporarily but can be called back to the cycle by external signals

• For example: liver cells are mostly non dividing but in response to signals (e.g. injuries) can start to divide again

What is a “Permanent G0 Phase”, what is an example of cells that might undergo this?

• Cells that are differentiated/highly specialized enter a permanent G0 arrest and can never divide again

• For example: nerve and muscle cells (Known as terminally differentiated)

Describe the DNA content as the cell cycle progresses.

• G1 = n

• S = 2n (DNA has been replicated)

• G2 = 2n

• M = Each daughter cell is 2n

What are mitogens?

• A class of growth factors that stimulate cells to grow and divide (Triggering cell cycle)

When are cells responsive to mitogens?

Only when they are in G1 (Considered start of cell cycle)

What does the presence of growth factors do to the cell?

pushes cell out of G1, to S, G2, M… etc.

The absence or withdrawal of mitogenic growth factors does what to a cell?

pushes cell from G1 to G0 (quiescence)

What are a couple examples of mitogens?

Platelet Derived Growth Factor (PDGF), Insulin Growth Factor (IGF), Epidermal Growth Factor (EGF)

Describe the mitogen trigger signaling pathway.

1.) Bind to a growth factor receptor

2.) Triggers a signal cascade to nucleus

3.) Drives cell cycle out of G1 to S phase

What two proteins regulate the cell cycle?

cyclins and cyclin dependent kinases (CDKs)

What must happen between cyclins and CDKs to activate target proteins (Furthermore how do they do this?)?

• Must form an active enzyme complex as they are inactive on their own

• Activate target proteins by phosphorylation

How are cyclins generated?

synthesized and degraded in a phase specific manner

How are CDKs generated?

not generated, are present throughout the cycle but are inactive until the appropriate cyclin has been synthesized for that particular part of the cell cycle

Which type of cyclin is the first to be activated (In G1 phase) by the mitogen interacting with the receptor?

cyclin D (Which complexes CDK-4-6)

• Active cyclin D/CDK-4-6 enzymes causes activation of target proteins

What is the purpose of checkpoints within the cell cycle?

surveillance systems which monitor that the events of the cell cycle progress as expected, blocking any cell cycle progression when conditions are unfavorable

What are the two important checkpoints in the cell cycle and what are they mediated by?

1.) G1 DNA damage checkpoint, mediated by p53 protein

2.) G1 Restriction point check mediated by pRb protein

p53 and pRb proteins are known as ______ ______.

tumour suppressors

Describe the process of p53 activation.

1.) DNA damage or mutations are recognized by the cell through a series of sensor proteins.

2.) Sensor proteins trigger the activation of p53 protein.

3.) Activated p53 triggers a cell cycle arrest (Allowing DNA to repair) or cell death/apoptosis

• Triggering either pathway means cells containing mutated or damaged DNA are not replicated

What happens if mutations are passed onto daughter cells?

can lead to genomic instability, leading to cancer

What is cellular senescence?

intrinsically programmed limit to cell proliferation

What is a “limited replicative potential” possessed by most cells?

after a period of cell division, most somatic cells undergo a permanent growth arrest termed replicative senescence or cellular senescence

Is senescence the same as G0?

NO, it cannot be reversed by growth factor stimulation, however the cells remain metabolically active

What other name does the ‘limit to cell growth’ go by? How did this phenomenon get first described?

Hayflick limit

• Cells grow rapidly (Phase 1)

• Growth is exponential (Phase 2)

• Cells stop growing, never able to enter the cell cycle again (Phase 3)

As we age what happens to our cells in terms of senescence?

the older we are, senescent cells increase in number, whereas a newborn for example may not have any at all

What are telomeres?

complexes of DNA that protein that “cap” linear chromosomes

• Made up of multiple repeats of sequence TTAGGG, most of telomere is double stranded, noncoding DNA

• It protects the chromosome from sticking together

How do telomeres regulate cell division?

• With each cell division, the end of the chromosome or the telomere is shortened

• The loss continues with each division until telomeres become very short

• When they become too short, it triggers cell to stop dividing and enter senescence

Why do the telomeres shorten?

• Due to the “end replication problem in DNA replication”

• When DNA replicates, there is a small gap at the end, arising with each round of cell division, thus shortening the telomere

With most cells, what does increasing cell division mean for the telomeres and cell division frequency?

the telomeres get shorter with cell division until cell stops dividing and enters senescence

Some cells can maintain telomere lengths throughout cell division, what are they termed and how do they do this?

• Signal to enter senescence is bypassed and cells can divide indefinitely, terming them immortal cells

What are some immortal cells?

cancer cells, stem cells, germ cells

Immortality is achieved by expression of an enzyme called _________. What can this enzyme do?

• Telomerase

• Can synthesize telomere DNA back onto the end of the chromosome so whilst the end of replication looses DNA, telomerase resynthesizes telomere DNA

Cell ____ and cell _____ must be finely ______ for an organ/animal’s homeostasis.

growth, death, balanced

What are the three main cell death pathways?

• Apoptosis

• Necrosis

• Autophagy

What are the three main reasons for a cell to engage in apoptosis?

List some examples of each.

1. Homeostasis (Normal tissue turnover)

   1. E.g. loss of uterus lining in menstruation

2. Animal Development

   1. Formation of fingers and toes of a fetus during embryonic development

   2. Required for resorption of the tadpole tail

   3. Required for involution of the mammary gland after weaning

3. As a Defense Mechanism

   1. Cells infected with viruses are killed via apoptosis, if this fails it can lead to a viral infection

   2. Cells carrying DNA mutations are killed via apoptosis

   3. Self reactive lymphocytes are destroyed by apoptosis, if this fails it can lead to autoimmune disease

What are some pro-apoptotic death signals?

• DNA damage (UV/Gamma/Chemotherapy)

• Growth factor (mitogen) withdrawal

• Hypoxia (Lack of oxygen)

• Ischaemia (Reduced blood flow)

What is the process of apoptotic cell death?

• Chromatin condenses, DNA fragments, resulting in regular size fragments of DNA produced

• Cytoplasm shrinks and membrane blebs

• Cell contents are packaged into membrane bound aptopic bodies

• Phospholipid phosphatidylserine is exposed on the surface

• Receptors on phagocytic cells (Macrophages) recognize exposed phospholipid and engulf cell fragments

What class of enzymes is important in apoptosis and why?

• Capases

• Activate nucleases (Cleave DNA) and proteases (Cleave protein) that bring about morphological changes in apoptic cells

What is necrosis?

a form of disordered cell death

What can cause necrosis?

• oxygen deprivation

• physical agents like mechanical trauma, extreme heat, radiation

• chemical agents or drugs

• viral or bacterial infections

Why is necrosis seen as a messy form of cell death?

• Cell contents spill out and elicit an immune response

• No capase activity associated

What is the process of nectrotic cell death?

• Chromatin clumps together

• Organelles and cell swell, plasma membrane ruptures

• Cell undergoes lysis, disintegrates

• Cell contents spill out into surroundings

• Immune response