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APOPTOSIS

Dr. Karzan Mohammad

Apoptosis - Definition

Cell death mechanisms
Death by suicide
Death by injury

APOPTOSIS

NECROSIS
NATURAL
YES
NO
EFFECTS
BENEFICIAL
DETRIMENTAL
Physiological or pathological
Always pathological
Single cells
Sheets of cells
Energy dependent
Energy independent
Cell shrinkage
Cell swelling
Membrane integrity maintained
Membrane integrity lost


APOPTOSIS
NECROSIS
Role for mitochondria and cytochrome C
No role for mitochondria
No leak of lysosomal enzymes
Leak of lysosomal enzymes
Characteristic nuclear changes
Nuclei lost
Apoptotic bodies form
Do not form
DNA cleavage
No DNA cleavage
Activation of specific proteases
No activation
Regulatable process
Not regulated
Dead cells ingested by neighboring cells
Dead cells ingested by neutrophils and macrophages

Significance of apoptosis

Between 50 and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a day.


Etiopathogenesis

Why should a cell commit suicide?

1. Programmed cell death is as needed for proper normal development as mitosis is. 2. Programmed cell death is needed to destroy cells that represent a threat to the integrity of the organism.

Incomplete differentiation in two toes due to lack of apoptosis

Apoptosis: importantance in adults
Tissue remodeling (eliminates cells no longer needed):
Virgin mammary gland
Late pregnancy, lactation
Involution (non-pregnant, non-lactating)
Apoptosis
Apoptosis
- Testosterone
Prostate gland


Apoptosis in pathological conditions - DNA damage - Accumulation of misfolded proteins - Cell death in certain infections

Cells infected with viruses One of the methods by which cytotoxic T lymphocytes (CTLs) kill virus-infected cells is by inducing apoptosis

Cancer cells Radiation and chemicals used in cancer therapy induce apoptosis in some types of cancer cells.

Morphological & Biochemical changes

Classic changes
Cell shrinkage Nuclear fragmentation Chromatin condensation Chromosomal DNA fragmentation Formation of cytoplasmic blebs& apoptotic bodies Phagocytosis

Mechanisms of apoptosis

Receptor pathway (physiological):
Death receptors: (FAS, TNF-R, etc)
FAS ligand
TNF
Death domains
Adaptor proteins
Pro-caspase 8 (inactive)
Caspase 8 (active)
Pro-execution caspase (inactive)
Execution caspase (active)
Death
MITOCHONDRIA

Apoptosis triggered by external signals: the extrinsic or death receptor pathway

Regulation of apoptosis
Regulatory proteins – BCL -2Apoptosis depends on binding of BCL -2 with pro apoptotic and anti apoptotic proteins.Situated in the outer mitochondrial membrane.Apaf -1Tp 53, caspases, BAX, viruses such as adeno, papilloma , hepatitis B.

Intrinsic pathway (damage):

Mitochondria
Cytochrome c release
Pro-caspase 9 cleavage
Pro-execution caspase (3) cleavage
Caspase (3) cleavage of cellular proteins, nuclease activation, etc.
Death
BCL-2 BCL-XL BCL-W MCL1 BFL1 DIVA NR-13 Several viral proteins

Intracellular signals

Oxidative damage from free radicals, Radiation, Virus infection, Nutrient deprivation, Pro-apoptotic Factors
Damage to the mitochondrial membrane increasing permeability
Entry of Cytochrome C into the cytoplasm
Cytochrome C binds to Apaf-1 forming an apoptosome
Apoptosome activates procaspase-9 to caspase-9
Caspase-9 cleaves and activates caspase-3 and caspase-7.
This executioner caspases activate a cascade of proteolytic activity that leads to: Chromatin condensation, DNA fragmentation, Protein cleavage, Membrane permeability

Apoptosis: Role in Disease Cancer

Apoptosis eliminates damaged cells (damage => mutations => cancer Tumor suppressor p53 controls apoptosis responses to damage. Most cancer cells are defective in apoptotic response(damaged, mutant cells survive)

Apoptosis: Role in Disease Cancer Virus associated cancer Several human papilloma viruses (HPV) have been implicated in causing cervical cancer. One of them produces a protein (E6) that binds and inactivates the apoptosis promoter p53. Epstein-Barr Virus (EBV), the cause of mononucleosis and associated with some lymphomas produces a protein similar to Bcl-2 produces another protein that causes the cell to increase its own production of Bcl-2. Both these actions make the cell more resistant to apoptosis (thus enabling a cancer cell to continue to proliferate).

Some B-cell leukemia and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals they may receive. Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1.

Apoptosis: Role in Disease Cancer

Other cancer cells express high levels of FasL, and can kill any cytotoxic T cells (CTL) that try to kill them because CTL also express Fas (but are protected from their own FasL). Some cancer cells, especially lung and colon cancer cells, secrete elevated levels of a soluble "decoy" molecule that binds to FasL, plugging it up so it cannot bind Fas. Thus, cytotoxic T cells (CTL) cannot kill the cancer cells
Apoptosis: Role in Disease Cancer

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