Apoptosis is inhibited by:
Ans. D. Bc12. (Ref. Robbin's pathology 8th/pg. 22)Robbin's pathology 8th/pg. 22 .........."The choice between cell survival and death is determined by the permeability of mitochondria, which is controlled by a family of more than 20 proteins, the prototype of which is Bcl-2.If cells are exposed to growth factors and other survival signals, they synthesize antiapoptotic members of the Bci- 2 family, the two main ones of which are Bcl-2 itself and Bcl-xL. These proteins antagonize Bax and Bak, and thus limit the escape of mitochondrial pro-apoptotic proteins. Cells deprived of growth factors not only activate the pro-apoptotic proteins but also show reduced levels of Bcl-2 and Bcl-xL, thus further tilting the balance toward death"Apoptosis* Programmed cell death; ATP required.* Characterized by:- Cell shrinkage,- Chromatin condensation (pyknosis),- Membrane blebbing,- DNA fragmentation (karyorrhexis),- Nuclear fragmentation (karyolysis),- No significant inflammation.- Formation of apoptotic bodies, (later phagocytosed). Necrosis;Verses, Apoptosis FeatureNecrosisApoptosis1Cell sizeEnlarged (swelling)Reduced (shrinkage)2NucleusPyknosis karyorrhexis karyolysisFragmentation into nucleosome-size fragments3Plasma membraneDisruptedIntact; altered structure, especially orientation of lipids4Cellular contentsEnzymatic digestion; may leak out of cellIntact; may be released in apoptotic bodies5Adjacent inflammationFrequentNo6Physiologic or pathologic roleInvariably pathologic (culmination of irreversible cell injury)Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage# Molecular aspect:- Mediated by caspases.* The activation of the caspase cascade is the most central step in apoptosis.0* Caspases can initiate apoptotic signals (caspases-8 and -9) and execute the apoptotic program (caspases-3, -6, -7).- Intrinsic mitochondrial pathway of apoptosis is the result of increased mitochondrial permeability and release of molecules like antiapoptotic family of Bcl-2 and Bcl-X and proapoptotic cytochrome 'C' and AIF.0- Cytochrome 'C\ well known for its role in mitochondrial respiration, in cytosol binds to a protein Apaf-land the complex activates caspase-9.- In apoptosis, Apaf-1 is activated by release Cytochrome C from the mitochondria.0Mitochondria are essential in controlling specific apoptosis pathways. The redistribution of cytochrome c, as well as apoptosis-inducing factor (AIF), from mitochondria during apoptosis leads to the activation of a cascade of intracellular proteases known as caspases. Caspase-independent apoptosis occurs after DNA damage, activation of poly-ADP-ribose polymerase, and translocation of AIF into the nucleus. Redistribution of cytochrome c is pre- vented by overproduction of the apoptotic protein BCL2 and is promoted by the proapoptotic protein BAX.# Occurs during:- Embryogenesis,- Hormone induction (menstruation),- Immune cell - mediated death,- Injurious stimuli (e.g., radiation, hypoxia),- Atrophy (e.g., endometrial lining during menopause).Additional Educational points: GeneAssociated tumor1ablCML2c-mycBurkitt's lymphoma3bcl-2Follicular and undifferentiated lymphomas (inhibits apoptosis)4erb-B2Breast, ovarian, and gastric carcinomas5rasColon carcinoma, pancreatic adenocarcinoma, thyroid cancer, and AML6L-mycLung tumor7N-mycNeuroblastoma8retMultiple endocrine neoplasia (MEN) types It and ill9c-kitGi stromal tumor (GIST)Representative Oncogenes at Chromosomal Translocations Gene (Chromosome)TranslocationMalignancy1ABL(9q34.1)-BCR (22q11)(9;22)(q34;q11)Chronic myelogenous leukemia2ATF1 (12q13)-EWS (22q12)(12;22)(q13;q12)Malignant melanoma of soft parts (MMSP)3BCL1 (11ql3.3)-IgH (14q32)(11;14)(q13;q32)Mantle cell lymphoma4BCL2 (18q21.3)-IgH (14q32)(14;18)(q32;q21)Follicular lymphoma5FLI1 (llq24)-EWS (22q12)(11;22)(q24;q12)Ewing's sarcoma6LCK (lp34)-TCRB (7q35)(1;7)(p34;q35)T cell acute lymphocytic leukemia (ALL)7C-MYC (8q24)-IgH (14q32)(8;14)(q24;q32)Burkitt's lymphoma, B cell ALL8WT1 (11p13)-EWS (22q12)(11;22)(p13;q12)Desmoplastic small round cell tumor (DSRCT)9PAX3 (2q35)-FKHR/ALV(13q14)(2;13)(q35;q14)Alveolar rhabdomyosarcoma10PAX7 (1p36)-KHR/ALV(13q14)(1;13)(p36;q14)Alveolar rhabdomyosarcoma11RET (10q11.2)(10;17)(q11.2;q23)Papillary thyroid carcinomas
p53
NMYC
ras
Bcl2
Cellular Pathology