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Apoptosis

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Abhishek Yadav

1. Apoptosis is a tightly regulated process of programmed cell death that removes unwanted or damaged cells. It involves activation of caspases and degradation of nuclear DNA and proteins. 2. There are two main pathways that initiate apoptosis - the extrinsic pathway which involves death receptors, and the intrinsic pathway which involves the mitochondria. Both pathways activate caspases that execute the cell death program. 3. Disorders of apoptosis can result in disease states like cancer if cells fail to undergo apoptosis in response to damage, or neurodegeneration if excessive apoptosis occurs. A delicate balance of pro-apoptotic and anti-apoptotic proteins regulates apoptosis.

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MODERATOR DR. POONAM MAAM LECTURER PATHOLOGY DEPTT. MRAMC PRESENTED BY : ABHISHEK KUMAR YADAV R.NO. - 04
oIntroduction oEtiopathogenesis oMorphological, Biochemical changes oMechanism oIntrinsic pathway oExtrinsic pathway oDisorders of apoptosis oConclusion
INTRODUCTION
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.
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.
ETIOPATHOGENESI S
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.
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
Apoptosis: in embryogenesis Morphogenesis (eliminates excess cells): Selection (eliminates non-functional cells):
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
Apoptosis: in immunity Immunity (eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells):
Apoptosis in pathological conditions - DNA damage - Accumulation of misfolded proteins - Cell death in certain infections - Pathological atrophy in parenchymal organs
MORPHOLOGICAL & BIOCHEMICAL CHANGES
CLASSIC CHANGES Cell shrinkage Nuclear fragmentation Chromatin condensation Chromosomal DNA fragmentation Formation of cytoplasmic blebs& apoptotic bodies Phagocytosis
Biochemical changes
MECHANISMS OF APOPTOSIS
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
Apoptosis
Initiation of apoptosis by activation of signalling pathways : There are two main signalling pathways in apoptosis : (A) Extrinsic/death receptor-initiated pathway :
(A) EXTRINSIC PATHWAY FLIP
Activation of caspase cascade Release of several mt proteins (B) INTRINSIC/MITOCHONDRIAL PATHWAY :
遺或鰻意禽
(B) INTRINSIC PATHWAY
Execution Phase
HISTOLOG Y
Apoptotic bodies Round oval mass of intensely eosinophilic cytoplasm
Apoptotic bodies Fragmented nuclei with condensed chromatin
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.
Apoptosis
DISORDERS OF APOPTOSIS
Apoptosis: Role in Disease TOO MUCH: Tissue atrophy TOO LITTLE: Hyperplasia Neurodegeneration Thin skin etc Cancer Athersclerosis etc
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.
Apoptosis
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
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).
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
ConClusion
DAMAGE Physiological death signals DEATH SIGNAL PROAPOPTOTIC PROTEINS (dozens!) ANTIAPOPTOTIC PROTEINS (dozens!) DEATH
Apoptosis

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Apoptosis

  • 2. oIntroduction oEtiopathogenesis oMorphological, Biochemical changes oMechanism oIntrinsic pathway oExtrinsic pathway oDisorders of apoptosis oConclusion
  • 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. 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.
  • 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. 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. Apoptosis: in embryogenesis Morphogenesis (eliminates excess cells): Selection (eliminates non-functional cells):
  • 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. Apoptosis: in immunity Immunity (eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells):
  • 12. Apoptosis in pathological conditions - DNA damage - Accumulation of misfolded proteins - Cell death in certain infections - Pathological atrophy in parenchymal organs
  • 14. CLASSIC CHANGES Cell shrinkage Nuclear fragmentation Chromatin condensation Chromosomal DNA fragmentation Formation of cytoplasmic blebs& apoptotic bodies Phagocytosis
  • 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
  • 19. Initiation of apoptosis by activation of signalling pathways : There are two main signalling pathways in apoptosis : (A) Extrinsic/death receptor-initiated pathway :
  • 21. Activation of caspase cascade Release of several mt proteins (B) INTRINSIC/MITOCHONDRIAL PATHWAY :
  • 26. Apoptotic bodies Round oval mass of intensely eosinophilic cytoplasm
  • 27. Apoptotic bodies Fragmented nuclei with condensed chromatin
  • 28. 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.
  • 31. Apoptosis: Role in Disease TOO MUCH: Tissue atrophy TOO LITTLE: Hyperplasia Neurodegeneration Thin skin etc Cancer Athersclerosis etc
  • 32. 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.
  • 34. 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
  • 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-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
  • 38. DAMAGE Physiological death signals DEATH SIGNAL PROAPOPTOTIC PROTEINS (dozens!) ANTIAPOPTOTIC PROTEINS (dozens!) DEATH