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Outline of Lecture
Cell death in living tissue
Necrosis (Not specified)
Apoptosis
Apoptosis
Programmed cell death-suicide
Cell membrane remains intact
No inflammatory reaction
Natural in physiological embryogenesis
Induced in therapeutic radiotherapy / chemotherapy
Examples physiologic apoptosis
During growth development & Embryogenesis.
Homeostatic mechanisms maintains cell population.
In aging
Shedding of menstrual endometrium
Involution of breast after weaning.
Apoptosis
Require activations signal →protein cleavage within cell causing cell death.
Programmed & energy dependent process designed to switch off & eliminate cells.
Cell shrinkage.
Chromatin condensation
Formation of cytoplasmic blebs & apoptotic bodies
Phagocytosis of apoptotic bodies.
Activation pathways
Intrinsic mitochondrial pathway
↑ mitochondrial membrane permeability → cytochrome c & AIF → activates caspases → death.
– 1.Withdrawal of GF
– 2.injury
Extrinsic death receptor pathway
– 1. FAS & TNF1 receptor families with death domain.
– 2. CTL CD8+
Intrinsic mitochondrial pathway
Examples withdrawal of positive signal.
– GF for neuron
– IL-2 for lymphocytes
Examples of receipt of negative signals.
– ↑ ICF oxidants
– UV light, X-rays, chemotherapeutic agents
– Misfolded proteins
– TNF-α, TNF-β (lymphokines).
– Fas-ligand (Fas-L)
Intrinsic mitochondrial pathway
Normal Bcl-2 on outer (M) membrane inhibit apoptosis.
In damaged cell Bax protein inhibits
(M ) Bcl-2 , & punches hole in (M) membane causing release of cytochrome-c into cytoplasm.
Cytochrome-c binds Apaf-1 (apoptotic protease activating factor-1)
Activates caspases 9→3 →7.
Intrinsic mitochondrial pathway (AIF)
Neuron does not use caspase
AIF located intermembrane space of mitochondria.
Released from mitochondria like in (1).
AIF migrates to nucleus.
Binds to DNA.
Triggers destruction of DNA.
Triggering apoptosis Extrinsic death receptor
(Receptor-L interaction)
FasL ,TNF receptor →caspase 8→ exec caspase.
CD8+CTL mediated lysis of their target cells.
Directly activates executioner caspases leading to apoptosis.
Does not use caspases cascade.
Apoptosis & cancer
HPV produces protein E6 which binds & inactivates apoptosis promoter p53.
EBV produces protein similar to Bcl-2 & ↑own Bcl-2 make infected cell more resistant to apoptosis.
B-cell lymphoma ↑ level of Bcl-2
Melanoma inhibit expression of Apaf-1
Colon & lung cancer cells produce blocking protein for Fas receptor CTL cannot kill these tumor cells.
Some cancer cell produce FasL which kill CTL directed against these tumor cells.
Apoptosis & Autoimmune system
Mutation is Fas , FasL or caspases result in auto reactive lymphocytes producing
Autoimmune Hemolytic anemia
Thrombocytopenia.
Apoptosis & AIDS
Normal CD4 count is 1000/µml of blood
AIDS
Apoptosis | howMed Lectures
This movie requires Flash Player 9
Outline of Lecture
Cell death in living tissue
Necrosis (Not specified)
Apoptosis
Apoptosis
Programmed cell death-suicide
Cell membrane remains intact
No inflammatory reaction
Natural in physiological embryogenesis
Induced in therapeutic radiotherapy / chemotherapy
Examples physiologic apoptosis
During growth development & Embryogenesis.
Homeostatic mechanisms maintains cell population.
In aging
Shedding of menstrual endometrium
Involution of breast after weaning.
Apoptosis
Require activations signal →protein cleavage within cell causing cell death.
Programmed & energy dependent process designed to switch off & eliminate cells.
Cell shrinkage.
Chromatin condensation
Formation of cytoplasmic blebs & apoptotic bodies
Phagocytosis of apoptotic bodies.
Activation pathways
Intrinsic mitochondrial pathway
↑ mitochondrial membrane permeability → cytochrome c & AIF → activates caspases → death.
– 1.Withdrawal of GF
– 2.injury
Extrinsic death receptor pathway
– 1. FAS & TNF1 receptor families with death domain.
– 2. CTL CD8+
Intrinsic mitochondrial pathway
Examples withdrawal of positive signal.
– GF for neuron
– IL-2 for lymphocytes
Examples of receipt of negative signals.
– ↑ ICF oxidants
– UV light, X-rays, chemotherapeutic agents
– Misfolded proteins
– TNF-α, TNF-β (lymphokines).
– Fas-ligand (Fas-L)
Intrinsic mitochondrial pathway
Normal Bcl-2 on outer (M) membrane inhibit apoptosis.
In damaged cell Bax protein inhibits
(M ) Bcl-2 , & punches hole in (M) membane causing release of cytochrome-c into cytoplasm.
Cytochrome-c binds Apaf-1 (apoptotic protease activating factor-1)
Activates caspases 9→3 →7.
Intrinsic mitochondrial pathway (AIF)
Neuron does not use caspase
AIF located intermembrane space of mitochondria.
Released from mitochondria like in (1).
AIF migrates to nucleus.
Binds to DNA.
Triggers destruction of DNA.
Triggering apoptosis Extrinsic death receptor
(Receptor-L interaction)
FasL ,TNF receptor →caspase 8→ exec caspase.
CD8+CTL mediated lysis of their target cells.
Directly activates executioner caspases leading to apoptosis.
Does not use caspases cascade.
Apoptosis & cancer
HPV produces protein E6 which binds & inactivates apoptosis promoter p53.
EBV produces protein similar to Bcl-2 & ↑own Bcl-2 make infected cell more resistant to apoptosis.
B-cell lymphoma ↑ level of Bcl-2
Melanoma inhibit expression of Apaf-1
Colon & lung cancer cells produce blocking protein for Fas receptor CTL cannot kill these tumor cells.
Some cancer cell produce FasL which kill CTL directed against these tumor cells.
Apoptosis & Autoimmune system
Mutation is Fas , FasL or caspases result in auto reactive lymphocytes producing
Autoimmune Hemolytic anemia
Thrombocytopenia.
Apoptosis & AIDS
Normal CD4 count is 1000/µml of blood
AIDS