Apoptosis

APOPTOSIS - Synchronized genetically controlled programmed cell death

1. Apoptosis by Rohan Pal M.Pharm (Pharmacology), 1 st year, 2 nd sem

2. 1. Definition 2. Purpose of Apoptosis 3. Morphological changes 4. Caspases 5. Initiation of Apoptosis 6. Mechanism of Apoptosis 7. Disorders of A poptosis 8. Conclusion Overview

3. Apoptosis may be defined as synchronized genetically controlled programmed cell death . Definition

4. Purpose of Apoptosis It’s essential for the proper development and to maintain homeostasis for the organism.

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

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

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

8. Mechanism of Apoptosis

9. Extrinsic Pathway TNF alpha, FAS ligand bind with its specific transmembrane receptor present on cell surface Activates its intracellular death domain, which recruits adaptor protein with death effector domain like FADD ( fas associated death domain) and TRADD FADD then associated with procaspase8 via dimerization of death effector domain At this point DISC (Death inducing signaling complex) is formed and activate caspase 8 COMMON PATHWAY

10. BCL2 Proteins:- 1.BH123 (pro apoptotic gene) = bax and bak 2. BCL2 ( anti-apoptotic gene) = Bcl2,Bcl-XL 3. BH3 only ( pro apoptotic gene) = bad,bim,bid,puma,noxa Intrinsic pathway

11. DNA damage ATM & ATRP sense the DNA damage and phosphorylate an enzyme cheakpoint kinase 1 & 2 This cheak point kinase add a phosphate group on p53 protein Activate pro apoptotic gene ( bak,bax,bid,bad,noxa,puma ) Puma / Noxa protein bind to anti apoptotic bcl2 protein Allow the binding of bak and bax and forming channel by which cytochrome C come out into cytosol Cytochrome C recruits apaf-1 (apoptotic protease activation factor) which recruits procaspase 9 this together called apoptosome Intrinsic pathway

12. Procaspase 9 converted into caspase 9 COMMON PATHWAY Intrinsic pathway

13. Viral infection The small pieces of viral protein complex with MHC-1 molecules and express on the surface of the cell T cytotoxic cells come to infected cell, they will recognize the viral proteins with the help of TCR and help of another molecule CD8,T cell will concern that is the antigen is associated with class 1 MHC molecules or not If molecules are associated with class 1 MHC molecules then TCR and CD8 both are activated and give signal to the cell through CD3 molecule Activated T cell release peptide chain which produce perforins on the surface of the infected cell Perforins pathway

14. Then T cytotoxic cell release granzymes and this granzymes enter into cell through this pores This granzymes activated executional caspases COMMON PATHWAY Perforins Pathway

15. Initiator caspases (8,9,10) Convert procaspase 3,6,7 to caspase 3,6,7 Activate Endonuclease CAD Degrades chromosomal DNA and chromatin condensation Executional caspases causes disintegration of the cells into apoptotic body Phagocytosis by macrophages Common Pathway

16. Overview of pathways

17. Disorders of apoptosis Apoptosis: Role in Disease

18. PARKINSON'S DISEASE ALZHEIMER'S DISEASE HUNTINGTON'S DISEASE Neurodegenerative Disease

19. Apoptosis eliminates damaged cells (damage => mutations => cancer Tumor suppressor p53 controls senescence and apoptosis responses to damage. Most cancer cells are defective in apoptotic response(damaged, mutant cells survive) High levels of anti-apoptotic proteins or Low levels of pro-apoptotic proteins ===> CANCER Apoptosis in Cancer

20. Aging --> both too much and too little apoptosis (evidence for both) Too much ---> tissue degeneration Too little ---> dysfunctional cells accumulate hyperplasia (precancerous lesions) Apoptosis: Role in Disease Aging

21. Cells are balanced between life and death Conclusion

22. 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) Albert's, Bruce, Alexander J., Julian L., Martin R., Keith R., Peter W. Molecular Biology of The Cell 4th Edition. Garland Science. pg. 1010-1014. Chiarugi and Markowitz. PARP-1--a perpetrator of apoptotic cell death? Science 297, p. 2008 Almas an, Alex. Cellular Commitment to Radiation-Induction Apoptosis. Department of Cancer Biology. pg. 347-350 Vol. 153 Issue 3 (March 2000) 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 Ejima , Kuniaki . Induction 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. References