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Apoptosis
- 1. MODERATOR DR. POONAM MA’AM LECTURER PATHOLOGY DEPTT. MRAMC PRESENTEDBY : ABHISHEK KUMAR YADAV R.NO. - 04
- 2. oIntroduction oEtiopathogenesis oMorphological, Biochemical changes oMechanism oIntrinsicpathway oExtrinsic pathway oDisorders of apoptosis oConclusion
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- 4. Apoptosis - Definition Apathway of cell death induced by a tightly regulated suicidal program, in which the cells destined to die activate enzymes that degrade cells own nuclear DNA and nuclear, cytoplasmic proteins.
- 5. Significance of apoptosis •During development → many cells produced in excess → programmed cell death → contribute to sculpturing of organs & tissues. • In human body about one lakh cells are produced every second by mitosis and a similar number die by apoptosis.
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- 7. Physiological apoptosis Programmed celldeath is as needed for proper normal development as mitosis is. Examples: • Formation of fingers & toes of fetus requires removal by apoptosis • Sloughing off of endometrium at the start of menstruation.
- 8. Apoptosis in physiologicsituations Programmed destruction during embryogenesis Involution of hormone dependent tissues Cell loss in proliferating cell populations Elimination of harmful self- reactive lymphocytes Death of host cells
- 9. Apoptosis: in embryogenesis Morphogenesis(eliminates excess cells): Selection (eliminates non-functional cells):
- 10. Apoptosis: importance inadults Tissue remodeling (eliminates cells no longer needed): Virgin mammary gland Late pregnancy, lactation Involution (non-pregnant, non-lactating) Apoptosis Apoptosis - Testosterone Prostate gland
- 11. Apoptosis: in immunity Immunity(eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells):
- 12. Apoptosis in pathologicalconditions - DNA damage - Accumulation of misfolded proteins - Cell death in certain infections - Pathological atrophy in parenchymal organs
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- 14. CLASSIC CHANGES • Cellshrinkage • Nuclear fragmentation • Chromatin condensation • Chromosomal DNA fragmentation • Formation of cytoplasmic blebs& apoptotic bodies • Phagocytosis
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- 17. STAGES OF CLASSICAPOPTOSIS Healthy cell DEATH SIGNAL / STIMULI (extrinsic or intrinsic) Commitment to die (reversible) EXECUTION (irreversible) Dead cell (condensed, crosslinked) ENGULFMENT (macrophages, neighboring cells) DEGRADATION
- 19. Initiation of apoptosisby activation of signalling pathways : There are two main signalling pathways in apoptosis : (A) Extrinsic/death receptor-initiated pathway :
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- 21. Activation of caspase cascade Release of severalmt proteins (B) INTRINSIC/MITOCHONDRIAL PATHWAY :
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- 26. Apoptotic bodies Roundoval mass of intensely eosinophilic cytoplasm
- 27. Apoptotic bodies Fragmentednuclei with condensed chromatin
- 28. REGULATION OF APOPTOSIS • Releaseof mitochondrial pro-apoptotic proteins tightly controlled by BCL2 family of proteins. • Antiapoptotic proteins : BCL2, BCLXL & MCL1 • Proapoptotic proteins : BAX and BAK • BCL2 sensor proteins : BAD, BIM, BID, Puma, Noxa (also called BH3 proteins) • Also, cytoplasm of normal cells contains inhibitors of apoptosis (IAP) which are neutralized by proapoptotic factors.
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- 31. Apoptosis: Role inDisease TOO MUCH: Tissue atrophy TOO LITTLE: Hyperplasia Neurodegeneration Thin skin etc Cancer Athersclerosis etc
- 32. Neurodegeneration →Neurons are post-mitotic. →Neuronaldeath caused by loss of proper connections, loss of proper growth factors (e.g. NGF), and/or damage (especially oxidative damage). →Neuronal dysfunction or damage results in loss of synapses or loss of cell bodies (synaptosis, can be reversible; apoptosis, irreversible) →PARKINSON'S DISEASE →ALZHEIMER'S DISEASE →HUNTINGTON'S DISEASE etc.
- 34. CANCER Apoptosis eliminatesdamaged 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
- 35. CANCER VIRUS ASSOCIATED CANCER •Human papilloma viruses (HPV) •causes cervical cancer •produces a protein (E6)-binds & inactivates apoptosis promoter p53. • Epstein-Barr Virus (EBV) - cause of mononucleosis and a/w 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).
- 36. • Some B-cellleukemia and lymphomas express high levels of Bcl-2 → block apoptotic signals. The high levels result from a translocation of BCL-2 gene into an enhancer region for antibody production. • Melanoma cells avoid apoptosis by inhibiting expression of the gene encoding Apaf-1. CANCER
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- 38. DAMAGE Physiological deathsignals DEATH SIGNAL PROAPOPTOTIC PROTEINS (dozens!) ANTIAPOPTOTIC PROTEINS (dozens!) DEATH