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Intercalated BSc 2007-08. CELL DEATH an overview. Dr Cathy Baker 22 nd October 2007. How do cells die?. Killed by injurious agents Induced to commit suicide. NECROSIS. APOPTOSIS. LEARNING OBJECTIVES. Understand, describe and illustrate … Differences: necrosis vs. apoptosis

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slide1
Intercalated BSc 2007-08

CELL DEATHan overview

Dr Cathy Baker

22nd October 2007

how do cells die
How do cells die?
  • Killed by injurious agents
  • Induced to commit suicide

NECROSIS

APOPTOSIS

learning objectives
LEARNING OBJECTIVES

Understand, describe and illustrate …

  • Differences: necrosis vs. apoptosis
  • Morphological changes of apoptosis
  • Function of apoptosis
  • Principal biochemical mechanisms
  • Role of apoptosis in pathologies
slide4
Necrosis

Apoptosis

Lecture overview

Function

Morphological

changes

Biochemistry

Pathology

necrosis
Necrosis
  • Mechanical injury & toxic agents
  • Cell groups
  • Membrane integrity destroyed
  • Cells and organelles swell, burst and leak contents
  • Inflammatory response
  • Other cells and tissues damaged
slide7
John Kerr et al

Br.J.Cancer 26: 239-257, 1972

apoptosis
Apoptosis
  • Essential biological process
  • Cells have role in own death - told or decide to commit suicide
  • Programmed cell death (PCD)
apoptosis1
Apoptosis
  • Distinct form of single cell death
  • Tightly regulated
  • Very localised
  • Energy consuming process
  • Membranes intact (early stages)
  • Safe disposal of cell corpse
  • No inflammation
slide10
Necrosis

Apoptosis

Morphological

changes

changes in cell morphology
Changes in cell morphology
  • Cells shrink and become detached from adjoining cells
  • Cytoskeleton collapses
  • Mitochondria remain intact
  • Plasma membrane develops bubbles (blebs) on surface
slide13
Nucleus and chromatin condense
  • Aggregates at periphery of nucleus
  • Nuclear envelope disintegrates
  • DNA fragmentation
  • Budding off and breakage into small membrane wrapped fragments - apoptotic bodies
what happens to apoptotic cells and apoptotic bodies
What happens to apoptotic cells and apoptotic bodies?
  • Ingested & degraded by phagocytes
  • Macrophages and dendritic cells
  • Adjacent cells in tissue
  • High speed and efficiency
  • Histologically inconspicuous
  • No inflammation
slide17
Necrosis

Function

Apoptosis

Morphological

changes

function of apoptosis
Function of apoptosis?
  • Deliberate removal of specific, unwanted cells
  • Organised and controlled manner
  • Without damaging other cells or tissues

Circumstances?

homeostasis
Homeostasis
  • Constancy of internal environment
  • Tissue turnover
  • Cell numbers have to be maintained

Homeodynamics

slide20
Embryonic development

Removal of unwanted cells

  • Damage
  • Organ and tissue differentiation
  • Vestigial structures
  • Alteration of tissue form
slide21
5 weeks

8 weeks

slide22
Neurologicaldevelopment
  • Deletion of excess immature neurons that have failed to establish synaptic connections
  • Occurs in CNS and PNS
  • Prevents redundant cell in mature nervous system
slide23
Involution of tissue
  • Endometrial breakdown prior to menstruation
  • Regression of lactating breast tissue after weaning
slide24
Cell damage
  • Internal cell damage
    • Inappropriate 3o protein structure
  • Cell Infection
    • Viral
  • Stress
    • Starvation
  • DNA damage
    • Ionizing radiation, ROS
slide25
Necrosis

Function

Apoptosis

Morphological

changes

Biochemistry

biochemistry of apoptosis
Biochemistry of apoptosis
  • Intense area of research
  • Complicated integrated mechanisms
  • Much more to be revealed!
  • Common core process
  • Underpins morphological changes
  • Four stage process
slide31
Stage 1- The Death Signal
  • Absence or withdrawal of positive survival factors
  • Presence of negative pro-apoptotic factors
survival or positive signals
Survival or positive signals
  • Cell survival relies receiving positive stimuli
  • Neuronal growth factor
  • Interleukin 2 for lymphocytes
  • Hormones
  • Withdrawal is a death signal
  • Default pathway for many cells
death or negative signals
Death or negative signals
  • Signals to induce apoptosis
  • Damaged DNA
    • UV light and X rays
    • Chemotherapeutic drugs
    • Oxidants/free radicals
  • Oxidative stress
  • Death activators or receptor ligands
what are death activators
What are Death Activators?
  • Molecules that bind to specific receptors on cell surface
    • Tumour necrosis factor alpha
    • Lymphotoxin TNF beta
    • Fas ligand (CD95)
  • Binding of death activator to its specific receptor is a pro-apoptotic signal
stage 2 integration and transduction
Stage 2 - Integration and Transduction
  • Signals linked to execution phase through an integration stage
  • Uses positive and negative regulatory molecules
  • Inhibit, stimulate or forestall apoptosis
to die or not to die
To die or not to die?

Integrated balance between positive survival factors and negative death signals decides fate of cell

common intracellular machinery for apoptosis
Common intracellular machinery for apoptosis

The three main players

  • Family of enzymes - Caspases
  • Protein family - Bcl-2 proteins
  • Regulating gene - p53 gene
caspases
Caspases
  • Family of protease enzymes
  • 14 isoforms identified
  • Have Cysteine at active site
  • Synthesised as inactive precursors - procaspase
  • Not all involved in apoptosis
slide39
cleavage

sites

prodomain

large subunits

small subunits

Procaspase structure

slide43
Initiator

caspases

Effector

caspases

Activated caspase has proteolytic activity

slide44
Activate other caspases
  • Amplify caspase activity

Initiator

caspases

Apoptosis

execution

Effector

caspases

bcl 2 proteins
Bcl-2 proteins
  • Large family of proteins
  • Named from B cell lymphoma
  • Some are pro-apoptotic some are anti-apoptotic
bcl 2 proteins and apoptosis
Bcl-2 proteins and apoptosis
  • Main mechanism is regulation of mitochondrial permeability
  • Cell survival stimuli induce the expression of anti-apoptotic Bcl proteins
  • Death signals induce pro-apoptotic Bcl proteins
p53 gene and p53 protein
p53 gene and p53 protein
  • p53 is tumour suppressor gene
  • Active gene product p53 produced in response to DNA and cell damage
  • Prevents cell completing cell cycle
  • If damage is minor - allows repair
  • If major - induces apoptosis
  • Complex mechanisms
apoptotic transduction pathways
Apoptotic transduction pathways
  • Mitochondrial or intrinsic pathway
  • Death activator or extrinsic pathway
slide52
Changes in trans-membrane potential
  • Pores form in (outer) membrane
  • Inner & outer membrane proteins involved

Bcl-2

Bax

slide53
Irreversible

cell death

Bcl-2

Bax

Cyt C

slide54
Cyt C

Apoptosis

activating factor -1

Apaf-1

slide57
ATP

Auto-activation of Procaspase - 9

slide58
ADP

Formation of Active Caspase -9

death receptor or extrinsic pathway
Death receptor or extrinsic pathway
  • Molecules that bind to specific receptors on cell surface
    • Tumour necrosis factor alpha (TNF)
    • Lymphotoxin TNF beta
    • Fas ligand (CD95)
  • Binding of death activator to specific receptor is pro-apoptotic signal - caspase activation
slide60
Binding sites for death activators

Death domains extending into cytosol

Cell membrane with specific death receptors

3 execution
3. Execution
  • Achieved through activation and deactivation of target proteins by effector caspases
activated effector caspases lead to
Activated effector caspases lead to …
  • Digestion of cytoskeleton proteins
  • Nucleus and chromatin degradation
  • Plasma membrane changes
chromatin degradation
Chromatin degradation
  • Caspase-9 enlarges nuclear pores
  • Allows entry of Caspase-3 and 7
  • Activation of nucleases
slide70
CAD

ICAD

Nucleosome

cleavage

Caspase Activated DNAase - CAD

slide71
CAD

Linker DNA

Nucleosome bead

8 histone molecules +

146 nucleotide pairs of DNA

slide74
mw ladder

DNA from

apoptotic cell

other nuclear changes
Other nuclear changes
  • Structural proteins - Lamins degraded by caspase-6
  • DNA repair enzymes inactivated
  • Nuclear membrane degraded
slide76
4. Cell removal

What is the eat me signal?

slide77
Enzyme system keeps PS on inner surface
  • Inhibited during apoptosis
  • PS redistributed to extra-cellular surface
  • Macrophage receptors recognise and bind PS
  • Phagocytosis of apoptosome
  • Release of anti-inflammatory substances
slide78
Necrosis

Function

Apoptosis

Morphological

changes

Biochemistry

Pathology

homeostasis1
Cell formation

Cell death

Homeostasis
  • Cell numbers have to be maintained
slide80
Uncontrolled growth of cells
  • Insufficient apoptosis
diseases featuring insufficient apoptosis
Diseases featuring insufficient apoptosis
  • Many cancers
  • Autoimmune Lymphoproliferative Syndrome (ALPS)
slide82
Excessive apoptosis
  • Uncontrolled cell loss
diseases featuring excessive apoptosis
Diseases featuring excessive apoptosis
  • Neurodegenerative
    • Parkinson’s disease
    • Alzheimer's disease
    • Amyotrophic lateral sclerosis (ALS)
    • Huntingdon’s disease
diseases featuring excessive apoptosis1
Diseases featuring excessive apoptosis
  • AIDS
    • Excessive apoptosis of T helper cells
  • Ischaemia
    • Cerebral caused by stroke
    • Cardiac caused by MI
you should now be able to
You should now be able to …

Understand, describe and illustrate …

  • Differences: necrosis vs. apoptosis
  • Morphological changes of apoptosis
  • Function of apoptosis
  • Principal biochemical mechanisms
  • Role of apoptosis in pathologies
ad