Apoptosis PDF

Balan • Tissue homeostasis mainly depends on the balance between cell proliferation and cell death. Programmed cell death or apoptosis is an intrinsic death program that occurs in various physiological and pathological situations . • Apoptosis or self destruction is necessary for normal development...

Balan • Tissue homeostasis mainly depends on the balance between cell proliferation and cell death. Programmed cell death or apoptosis is an intrinsic death program that occurs in various physiological and pathological situations . • Apoptosis or self destruction is necessary for normal development and homeostasis of multicellular organisms. Apoptosis plays a major role in many diseases like cancer, AIDS and neurodegenerative disorders. Cell death • Cell die by one of two mechanisms- Necrosis - Death By Injury - Apoptosis - Death By Suicide • Apoptosis and necrosis have different characteristics Need Of Apoptosis • Apoptosis is needed for proper development Examples: The resorption of the tadpole tail The formation of the fingers and toes of the fetus The formation of the proper connections between neurons in the brain • Apoptosis is needed to destroy cells Examples: Cells infected with viruses Cells with DNA damage Cancer cells Reasons of apoptosis • Withdrawal of positive signals a examples : – growth factors for neurons – Interleukin-2 (IL-2) • Receipt of negative signals examples : – increased levels of oxidants within the cell – damage to DNA by oxidants – death activators : • Tumor necrosis factor alpha (TNF-α) • Lymphotoxin (TNF-β) • Fas ligand (FasL) a Inducers of Apoptosis e • TNF family • Growth factor withdrawl I • Calcium • Oncogenes • Nutrient deprivation • Toxins • UV radiation • Gamma radiation I’m Caspase Role in Apoptosis • • • • • • • Cut off contact with surrounding cells Reorganize cytoskeleton Shut don DNA replication and repair Interrupt splicing Destroy DNA Disrupt nuclear structure Induce cell to display signals marking it for phagocytosis • Disintegrate cells into apoptotic bodies Types Two types: - those involved in apoptosis: Initiators – activate downstream effector caspases to initate Is activation cascades: Caspases2 Caspases9 Caspases8 Caspases10 Effectors - cleave target proteins resulting in morphological and biochemical markers of apoptosis: Caspases3 Caspases6 Caspases7 Caspases14 Intrinsic Pathway BITE • Initiated from within the cell. • Activated in response to signals such as DNA damage, loss of cell survival factors ,cell stress. • Hinges on balance brtween pro and antiapoptotic signals of Bcl-2 family. • Apaf-1,cytochrome-c,ATP(apoptosome) activate procaspase-9 complex. • pro apoptotic proteins released which activate caspase proteases Extrinsic Pathway • Begins outside the cells. • Activation of death receptors (Fas-R,TNF-R ,DR3,DRY/DR5) by death ligands (Fas-L,TNFalpha,Apo3L,Apo2L)play major role. • Death induced signalling compex (DISC) activated. • On DISC activation same effctor pathway as intrinsic pathway is adopted AIDS Autoimmune deficiency syndrome (AIDS) is an example of an autoimmune disease that results from infection with the human immunodeficiency virus (HIV) . This virus infects CD4+ T cells by binding to the CD4 receptor. The virus is subsequently internalized into the T cell where the HIV Tat protein is thought to increase the expression of the Fas receptor, resulting in excessive apoptosis of T cells . A So what kills so many uninfected CD4+ cells? Answer is: Apoptosis. There are several possibilities. One of them:  All T cells, both infected and uninfected, express Fas.  Expression of a HIV gene (called Nef) in a HIVinfected cell causes  The cell to express high levels of FasL at its surface  While preventing an interaction with its own Fas from causing it to self-destruct.  However, when the infected T cell encounters an uninfected one (e.g. in a lymph node), the interaction of FasL with Fas on the uninfected cell kills it by apoptosis.