Apoptosis

By Erika Amberson

Cell Suicide:

Overview of research into apoptosis

• 1800s Observation of cell death

• 1908 Mechnikov wins Nobel prize for phagocytosis

• 1930-40 Studies of metamorphosis

• 1948-49Cell death in chick limb

• 1955 Beginning of studies of lysomes

• 1964-66 Necrosis & PCD described

• 1971 Apoptosis term established

• 1977 Cell death genes in C. elegans discovered

• 1980-82 Caspase-3 (ced-3) identified

• 1989-91 Apoptosis genes identified, ced-3 sequenced

(Richerd et.al., 2001)

What is Apoptosis?

• Programed cell death• Orderly demise of cell• Essential for multi-cellular

organisms survival during cell division

• Important for cellular development

Ex: Finger webbing in humans

• Body produce millions more cells than needed

• Cells that do not form synaptic connections undergo apoptosis

• Some cases cells do not undergo cell death, webbing remains

Necrosis vs. Apoptosis

Cell death by injury• Cells swell

• Membrane rupture

• Cell lyses occurs

• Inflammation

• Mechanism- APT depletion, membrane injury, free radical damage

• Areas of tissues are affected

Cell death by suicide• Cell shrinkage

• Membrane remain intact

• Cell is phagocytosed

• No inflammation

• Mechanism – capases activated, endonuclease and proteases

• Individual cell affected

Necrosis Vs. Apoptosis

Wilde, 1999

Stages of Apoptosis

1. Cell damaged, stressed, or trigged by body signal

2. Mitochondrial leakage

3. Cell shrinkagea) Chromatin condensationb) Nuclear fragmentation

4. Enzymatic breakdown (membrane blebbing)

5. Nucleus destroyed

6. Phagocytosis occurs

Caspase: Cysteine-aspartic proteases

• Essential role in apoptosis, necrosis and inflammation

• Required for immune system in maturation of lymphocytes

• Aids in cell differentiation & proliferation

Pathways

Extrinsic Pathway• Death receptor

• Initiated from outside the cell

• Activated through pro-apoptotic receptors (ligands) on cell surface

Intrinsic Pathway• Mitochondrial

• Initiated from within the cell

• Activated in response to signals from DNA damage (cell stress)

• Binding of Fas by Fas ligand induces recruitment

of Fas protein

• Inside of cell Fas protein recruits adaptor protein that bind procaspase 8

• Caspase-8 is activated

• Caspase-8 activates Caspase-3

• Caspase -3 cleaves other proteins

• Signal cascade occurs releasing Cytochrome- c from the mitochondria activating ApaF-1

• ApaF-1 binds with Caspase-9 creating an Apoptosome

• Apoptsome activates Caspase-3 which cleaves the actin cytoskeleton and apoptosis occurs

• Absence of Tropic Factor from trophic factor receptor

• p53 protein phosphorylated

• Inhibiting Bcl-2 & Bcl-XL releasing pro-apoptotic regulator Bax

• Cytochrome c is released and binds ApaF-1

• ApaF-1 binds with procaspase-9 activating the caspase cascade

• ApaF-1 binds with Caspase-9 creating an Apoptosome

• Apoptsome activates Caspase- 3 which cleaves the actin cytoskeleton and apoptosis occurs

Diseases associated with Apoptosis

Inhibits Apoptosis• Cancer

• HPV• Melanoma

• Autoimmune Disorders• Systemic Lupus• Immune-mediate glomerulonephritis

• Viral Infections• Herpes

Increases Apoptosis• AIDS

• Neurodegenerative Disorders• Alzheimer’s Disease• Parkinson’s Disease

• Ischemic Injury• Stroke• Myocardial infarction

• Toxin-Induced liver disease• Alcohol

Future research…….

• How cells are selected in vivo for cell death

• How effector caspases are able to trigger apoptosis specifically for targeted cells and not elicit a full blow apoptotic response

• Further understanding of cell death regulations to help treat a variety of human disorders that are specific to programmed cell death