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Apoptosis

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Apoptosis - Programmed Cell Death

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Apoptosis

  1. 1. MODERATOR DR. POONAM MA’AM LECTURER PATHOLOGY DEPTT. MRAMC PRESENTED BY : ABHISHEK KUMAR YADAV R.NO. - 04
  2. 2. oIntroduction oEtiopathogenesis oMorphological, Biochemical changes oMechanism oIntrinsic pathway oExtrinsic pathway oDisorders of apoptosis oConclusion
  3. 3. INTRODUCTION
  4. 4. Apoptosis - Definition A pathway 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. 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.
  6. 6. ETIOPATHOGENESI S
  7. 7. Physiological apoptosis Programmed cell death 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. 8. Apoptosis in physiologic situations  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. 9. Apoptosis: in embryogenesis Morphogenesis (eliminates excess cells): Selection (eliminates non-functional cells):
  10. 10. Apoptosis: importance 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
  11. 11. Apoptosis: in immunity Immunity (eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells):
  12. 12. Apoptosis in pathological conditions - DNA damage - Accumulation of misfolded proteins - Cell death in certain infections - Pathological atrophy in parenchymal organs
  13. 13. MORPHOLOGICAL & BIOCHEMICAL CHANGES
  14. 14. CLASSIC CHANGES • Cell shrinkage • Nuclear fragmentation • Chromatin condensation • Chromosomal DNA fragmentation • Formation of cytoplasmic blebs& apoptotic bodies • Phagocytosis
  15. 15. Biochemical changes
  16. 16. MECHANISMS OF APOPTOSIS
  17. 17. STAGES OF CLASSIC APOPTOSIS Healthy cell DEATH SIGNAL / STIMULI (extrinsic or intrinsic) Commitment to die (reversible) EXECUTION (irreversible) Dead cell (condensed, crosslinked) ENGULFMENT (macrophages, neighboring cells) DEGRADATION
  18. 18. Initiation of apoptosis by activation of signalling pathways : There are two main signalling pathways in apoptosis : (A) Extrinsic/death receptor-initiated pathway :
  19. 19. (A) EXTRINSIC PATHWAY FLIP
  20. 20. Activation of caspase cascade Release of several mt proteins (B) INTRINSIC/MITOCHONDRIAL PATHWAY :
  21. 21. CONTD…
  22. 22. (B) INTRINSIC PATHWAY
  23. 23. Execution Phase
  24. 24. HISTOLOG Y
  25. 25. Apoptotic bodies  Round oval mass of intensely eosinophilic cytoplasm
  26. 26. Apoptotic bodies  Fragmented nuclei with condensed chromatin
  27. 27. REGULATION OF APOPTOSIS • Release of 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.
  28. 28. DISORDERS OF APOPTOSIS
  29. 29. Apoptosis: Role in Disease TOO MUCH: Tissue atrophy TOO LITTLE: Hyperplasia Neurodegeneration Thin skin etc Cancer Athersclerosis etc
  30. 30. Neurodegeneration →Neurons are post-mitotic. →Neuronal death 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.
  31. 31. CANCER  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
  32. 32. 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).
  33. 33. • Some B-cell leukemia 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
  34. 34. ConClusion
  35. 35. DAMAGE Physiological death signals DEATH SIGNAL PROAPOPTOTIC PROTEINS (dozens!) ANTIAPOPTOTIC PROTEINS (dozens!) DEATH

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