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By: Thinh Le

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Introduction <ul><li>The word apoptosis was introduced by Kerr, Wyllie and Currie to describe a form of cell death distinct from necrosis. </li></ul><ul><li>Apo = [ Greek ] : from, separation from; Ptosis= [ Greek ] : dropping, a falling down </li></ul>

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Apoptosis vs Necrosis Apoptosis • Chromatin condensation • Cell Shrinkage • Preservation of Organelles and cell membranes • Rapid engulfment by neighboring cells preventing inflammation Necrosis • Nuclear swelling • Cell Swelling • Disruption of Organelles • Rupture of cell and release of cellular contents • Inflammatory response 1972 Kerr Wyllie Currie

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Evolution of the Origin of Programmed Cell Death (PCD) <ul><li>Mitochondria retain their collection of molecule that can trigger cell suicide after the enter the stabilize in the eukaryotic cell. </li></ul><ul><li>This process has evolved to occur only when programmed. </li></ul>

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Purpose of Apoptosis <ul><li>It’s essential for the proper development and to maintain homeostasis for the organism. </li></ul>

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Inititation <ul><li>DNA damage within the cell. </li></ul><ul><li>Cancerous cells </li></ul><ul><li>Cells of the immune system after they have fulfilled their function </li></ul><ul><li>Ionizing Radiation </li></ul><ul><li>Stress and infection such as virus </li></ul>Types of Induction: Cell surface death receptor mediated pathway (extrinsic) Mitochondrial-initiated pathway (intrinsic)

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Caspases <ul><li>Family of Proteins- main executors of the apoptotic process. </li></ul><ul><li>They belong to a group of enzymes known as cysteine proteases. </li></ul><ul><ul><li>Zymogens- inactive forms </li></ul></ul><ul><li>Caspase 8 and 10- initiator (extrinsic) </li></ul><ul><li>Caspase 9- initiator (intrinsic) </li></ul><ul><ul><li>Lead to effector caspase 3 and 6 </li></ul></ul><ul><ul><ul><li>Cleave key cellular proteins </li></ul></ul></ul>

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Other Important Proteins <ul><li>Blc-2 family helps regulate the activation of procaspases. </li></ul><ul><ul><li>Inhibitors - Bcl-2, Bcl-X L </li></ul></ul><ul><ul><li>Promoters – Bad, Bax, Bak </li></ul></ul>

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Mechanism (Extrinsic) <ul><li>Death Receptors- cell surface receptor that transmit apoptotic signals, initiated by ligands. </li></ul><ul><ul><li>Ligands: Fas ligand, Tumor Necrosis Factor (TNF) alpha, and Tumor necrosis (TNF)-related apoptosis-inducing ligand TRAIL. </li></ul></ul><ul><li>Lead to generation of ceramide </li></ul><ul><ul><li>Result in large number of clustering of death receptors. </li></ul></ul><ul><ul><ul><li>This helps strengthen the apoptotic signaling. </li></ul></ul></ul><ul><li>Death domain </li></ul><ul><ul><li>Conformation change in the intracellular domain of the receptor. </li></ul></ul><ul><ul><li>Allows recruitment of various apoptotic proteins to the receptor. </li></ul></ul>

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Death Inducing Signaling Complex

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Mechanism (Extrinsic) cont. <ul><li>Final step- recruitment of caspase 8 </li></ul><ul><ul><li>Resulting the activation of caspase 8 and the initiation of apoptosis. </li></ul></ul>

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Mechanism (Extrinsic) cont.

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Mechanism (Intrinsic) <ul><li>Mitochondria contains proteins like Apoptosis Inducing Factor (AIF), Smac/ DIABLO and Cytochrome C that regulate cell death. </li></ul><ul><li>These proteins are release through the a pore called Permeability Transition (PT) pore </li></ul><ul><ul><li>Form by pro-apoptotic members of Bcl-2 family (activated by apoptotic signals) </li></ul></ul><ul><li>The release of Cytochrome leads to recruitment of pro-caspase 9 and Apoptotic protease activating factor 1 ( Apaf-1). </li></ul><ul><ul><li>This forms the apoptosome </li></ul></ul>

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Mechanism (Intrinsic) cont. <ul><li>This is follow by the activation of caspase 9 which in turn result with the induction of apoptosis. </li></ul>

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Mechanism (Intrinsic) cont.

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Review

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Conclusion

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References <ul><li>Albanese, Joseph, Nicholas D. Ionizing Radiation Alters Fas Antigen Ligand at the Cell Surface and on Exfoliated Plasma Membrane-Derived Vesicle: Implications for Apoptosis and Intercellular Signaling . Yale University School of Medicine. Radiation Research pg. 49-61 (2000) </li></ul><ul><li>Alberts, Bruce, Alexander J., Julian L., Martin R., Keith R., Peter W. Molecular Biology of The Cell 4 th Edition. Garland Science. pg. 1010-1014. Chiarugi and Moskowitz. PARP-1--a perpetrator of apoptotic cell death? Science 297, p. 2008 </li></ul><ul><li>Almasan, Alex. Cellular Commitment to Radiation-Induction Apoptosis . Department of Cancer Biology. pg. 347-350 Vol. 153 Issue 3 (March 2000) </li></ul><ul><li>Bruchhaus, Iris. Protozoan parasites: Programmed Cell Death as a Mechanism of parasitism . Bernhard Nocht Inst. Trop. Medicine. Trends in Parasitology 23, no. 8 (August 2007):376-383 </li></ul><ul><li>Ejima, Kuniaki. Inductionn of Apoptosis in Placentas of Pregnant Mice Exposed to Lipopolysaccharides: Possible Involvement of Fas/Fas Ligand System. University of Occupational and Environmental Health. Biology of Reproduction 62, 178-185 . 17 May 1999. </li></ul><ul><li>Park, HeonJoo. Apoptosis and Cell Cycle Progression in an Acidic Environment After Irradiation . University of Minnesota Medical School. Radiation Research pg. 295-304 vol. 153:3 (March 2000) </li></ul>