<prompt> Apoptosis is inhibited by:p53NMYCrasBcl2  <response>: Ans. D. Bc12. Ref. Robbins pathology 8thpg. 22Robbins pathology 8thpg. 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 deathApoptosis 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 swellingReduced shrinkage2NucleusPyknosis 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 injuryOften 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-mycBurkitts lymphoma3bcl-2Follicular and undifferentiated lymphomas inhibits apoptosis4erb-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 GISTRepresentative Oncogenes at Chromosomal Translocations Gene ChromosomeTranslocationMalignancy1ABL9q34.1-BCR 22q119;22q34;q11Chronic myelogenous leukemia2ATF1 12q13-EWS 22q1212;22q13;q12Malignant melanoma of soft parts MMSP3BCL1 11ql3.3-IgH 14q3211;14q13;q32Mantle cell lymphoma4BCL2 18q21.3-IgH 14q3214;18q32;q21Follicular lymphoma5FLI1 llq24-EWS 22q1211;22q24;q12Ewings sarcoma6LCK lp34-TCRB 7q351;7p34;q35T cell acute lymphocytic leukemia ALL7C-MYC 8q24-IgH 14q328;14q24;q32Burkitts lymphoma, B cell ALL8WT1 11p13-EWS 22q1211;22p13;q12Desmoplastic small round cell tumor DSRCT9PAX3 2q35-FKHRALV13q142;13q35;q14Alveolar rhabdomyosarcoma10PAX7 1p36-KHRALV13q141;13p36;q14Alveolar rhabdomyosarcoma11RET 10q11.210;17q11.2;q23Papillary thyroid carcinomas 