Apoptosis

Question 1

2 processes of cell death

Answer 1

Apoptosis: programmed cell death that is a normal and necessary event of normal development. Triggered by variety of signals

Necrosis: death due to unexpected and accidental cell damage.
o Eg. toxins, radiation, heat, trauma, hypoxia

Question 2

necrosis

Answer 2

As necrotic cells die, they:
o swell
o holes appear in the plasma membrane
o intracellular materials spill out into the surrounding environment.
o Causes tissue damage, inflammation, oedema, recruitment of WBC’s.

Question 3

apoptosis

Answer 3

• fragmentation of chromosomes
• organelle disruption
• fragmentation of cell
• sequential destruction of cell

Question 4

apoptosis vs necrosis

Answer 4

active vs passive
physiol/path vs path
no inflam vs inflam
cell shrinkage vs swelling
marked condensation cr vs DNA degradation
preserved organelles vs swelling of mito
condensation of cytoplasm vs breakdown of CM
release of membrane bound fragments vs loss of ion transport
fragments removed by phagocytosis vs cell lysis & dissipation

Question 5

cell death and its regulation

Answer 5

• Cells have intrinsic apoptosis pathways for suicide without the release of cytosolic contents.
• Apoptosis is crucial for normal development.
• Cells require trophic factors that bind to surface receptors to repress apoptosis for survival.
• Apoptosis involves activation of cellular caspase proteases that cleave cellular proteins.
• Death signals murder cells by activating apoptosis.

Question 6

apoptosis

Answer 6

• Is required for many normal functions:
• Embryogenesis
  o Morphogenesis & cell selection
• Immunity - removal of immature B lymphocytes
• Tissues Remodeling
• Maintaining organ size and shape
• Also provides protection against cancer:
  o p53, a tumor suppressor protein
  o induces apoptosis

Question 7

apoptosis in embryogenesis

Answer 7

• morphogenesis: eliminated excess cells
• immunity: eliminated dangerous cells
• selection: eliminates non-functional cells (nerves that can’t form connections)
• organ size: eliminates excess cells

Question 8

apoptosis in adults

Answer 8

• tissue remodelling: eliminates cells no longer needed, lymphocytes pointed to die by apoptosis
• maintains organ size and function: cells lost by apoptosis are replied by cell division

Question 9

factors that induce apoptosis

Answer 9

• Activation of receptors: Some signal transduction pathways induce apoptosis
• Attack by cytotoxic T lymphocytes: These cells transfer serine proteases and other lytic components that permeabilises membrane.
• Action of the tumour suppressor p53 protein: This protein allows death of a cancerous cell by inducing apoptosis (p53 induces apoptosis)

Question 10

apoptosis and cell cycle control

Answer 10

• Driven by activity of caspases*
• cysteine-containing aspartate-specific proteases
• normally present as inactive zymogens (harmless to cell)
• zymogen is activated by proteolysis,
  oie. bit cleaved off
• active caspases then target other proteins for destruction
• *CASPASES = PROTEASES
• ***Caspase 3 (most important caspase)

Question 11

experiment to identity key proteins

Answer 11

Programmed cell death plays a central role in the development of most multicellular animals.

Question 12

stages of classic apoptosis

Answer 12

1. Healthy cell
2. Exposed to number of triggers
3. CED9 switched off
4. Stops blocking CED3 (CED3 stimulates apoptois
5. As a result Caspase 3 expressed
6. Dead cell

Question 13

rule of Red proteins for apoptosis in C. elegenas

Answer 13

• Ced = C. elegans death proteins
• Ced-3 is a caspase that induces apoptosis.
• synthesized as a Zymogen (an inactive form)
• activated by Ced-4
• Ced-9 complexes with Ced-4 and localizes it on the mitochondrial membrane.
• Availability of Ced-4 in the cytoplasm depends on the concentration of Ced-9.

Question 14

activation mechanisms of apoptosis

Answer 14

• The initiation of apoptosis is tightly regulated by activation mechanisms, because once apoptosis has begun, it inevitably leads to the death of the cell.
  Two mechanisms:
  o Extrinsic: activated by extracellular ligands binding to cell-surface death receptors
  o Intrinsic: activated by intracellular signals generated when cells are stressed (mitochondria)

Question 15

role of mitochondria in apoptosis

Answer 15

• Initiating role
• Role of cytochrome c in apoptosis. Cytochrome c is a small, soluble, mitochondrial protein, located in the inter membrane space, that carries electrons between Complex III and Complex IV during respiration. In a completely separate role, as outlined here, it acts as a trigger for apoptosis by stimulating the activation of a family of proteases called caspases.

Question 16

control of apoptosis

Answer 16

extrinsic pathway (physiological receptor) and intrinsic pathway (internal damage) –> mitochondrial signals –> caspase cleavage cascade –> orderly cleavage of proteins and DNA –> cross linking of cell corpses; engulfment (no inflammation)

Question 17

consequences of dysregulation

Answer 17

If not regulated properly, apoptosis causes a variety of diseases that include:
o cancer 
o autoimmune diseases and 
o neurodegenerative diseases, 
o Eg. Alzheimer's, Huntington's, and ALS

These diseases involve either:
o a failure of apoptosis to eliminate harmful cells e.g. in cancer or
o the inappropriate activation of apoptosis leading to loss of essential cells.

Question 18

apoptosis role in disease

Answer 18

TOO MUCH: Tissue atrophy
o Neuro-degeneration
o Thin skin, etc

TOO LITTLE: Hyperplasia
o Cancer
o Atherosclerosis, etc

Question 19

neuro-degeneration

Answer 19

• Neurons are post-mitotic (cannot replace themselves;
• neuronal stem cell replacement is inefficient)
• Neuronal death caused by loss of proper connections,
• loss of proper growth factors (e.g. NGF), and/ordamage (especially oxidative damage)
• Neuronal dysfunction or damage results in loss of synapses or loss of cell bodies
• (synaptosis, can be reversible; apoptosis, irreversible)
• Parkinson’s disease
• Alzheimer’s disease
• Huntington’s disease etc.

Question 20

cancer

Answer 20

• Apoptosis eliminates damaged cells
  (damage –> mutations–> cancer)
• Tumor suppressor p53 controls senescence and apoptotic responses to damage
• Most cancer cells are defective in apoptotic response (damaged, mutant cells survive)
• High levels of anti-apoptotic proteins or Low levels of pro-apoptotic proteins –> CANCER

Question 21

ageing

Answer 21

• Aging –> both too much and too little apoptosis (evidence for both)
• Too much (accumulated oxidative damage?) –> tissue degeneration
• Too little (defective sensors, signals? –> dysfunctional cells accumulate hyperplasia (pre-cancerous lesions)