Programmed Cell Death (Apoptosis) PDF

Programmed cell death (Apoptosis) Nidhika M.Pharm. (Pharmacology) IInd sem. Introduction • Apoptosis, or programmed cell death, is a highly regulated process that allows a cell to self-degrade in order for the body to eliminate unwanted or dysfunctional cells. During apoptosis, the genome of the c...

Programmed cell death (Apoptosis) Nidhika M.Pharm. (Pharmacology) IInd sem. Introduction • Apoptosis, or programmed cell death, is a highly regulated process that allows a cell to self-degrade in order for the body to eliminate unwanted or dysfunctional cells. During apoptosis, the genome of the cell will fracture, the cell will shrink and part of the cell will disintegrate into smaller apoptotic bodies. • Between 50 and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a day. normall but infecti e History • German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1845, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. • Kerr received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14, 2000, for his description of apoptosis. He shared the prize with Boston biologist Robert Horvitz. • The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, Horvitz and John E. Sulston for their work identifying genes that control apoptosis. The genes were identified by studies in the nematode C. elegans and these same genes function in humans for apoptosis. • Apoptosis has since been recognized and accepted as a distinctive and important mode of “programmed” cell death, which involves the genetically determined elimination of cells. • Apoptosis is essential to embryonic development and the maintenance of homeostasis in multicellular organisms. In humans, for example, the rate of cell growth and cell death is balanced to maintain the weight of the body. During fetal development, cell death helps sculpt body shape and making the right neuronal connections. 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 NECROSIS Vs APOPTOSIS My ed g t 0 a I APOPTOSIS ( Physiological cell death) NECROSIS ( Pathological cell death) Functional form of cell death Accidental form of cell death Occurs under physiological conditions Seen under pathological conditions Energy (ATP)- dependent No energy requirement 4g R Cell shrinks and pulls away from its Cell swelling in a defining features neighbours Nucleus ruptures Entire cell balloons and ruptures Induced by physiological stimuli( lack of Induced by non-physiological disturbances growth factor, changes in harmonal lytic viruses, hypothermia,hypoxia, environment ischaemia,metabolic poisons No inflammation follows apoptosis Necrosis is followed by inflammation 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 Incomplete differentiation due to lack of Apoptosis 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 __ To mar y Thymus maturation b cytokines b Antibody Inducers of Apoptosis e • TNF family • Growth factor withdrawl I • Calcium • Oncogenes • Nutrient deprivation • Toxins • UV radiation • Gamma radiation I’m Apoptosis in physiological conditions In human body about 100,000 cells are produced every second by mitosis and a similar no. die by apoptosis • Important in normal physiology – Development: Immune systems maturation, Morphogenesis, Neural development – Adult: Immune privilege, DNA Damage and wound repair. • Excess apoptosis – Neurodegenerative diseases • Deficient apoptosis – Cancer – Autoimmunity Caspases • Caspases stands for cysteine aspartate-specific protease. • Caspases have the characteristics of high specificity for substrates containing Asp, and use a Cys for catalyzing peptide bond cleavage. • Synthesized in the cell as precursors named procaspase. e • Caspases are the major executioners in apoptosis. Caspase Structure • • • O NH2-terminal domain Large subunit (~20kD) Small subunit (~10kD) Caspase Activation e inflamation more when expressed 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 µ's 1st Apoptosis: Pathways “Extrinsic Pathway” Death Ligands Death Receptors “Intrinsic Pathway” DNA damage & p53 Mitochondria/ Cytochrome C Initiator Caspase 8 Effector Caspase 3 a Initiator Caspase 9 O PCD Fdical marker o so 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 f Bd 2 O O O Ing Disorders where apoptosis is inhibited (decreased apoptosis,increase in cell survival) 1.Cancer Colorectal cancer Glioma Liver Lymphoid malignancies Neuroblastoma Prostate cancer Follicular lymphomas Carcinomas with p-53 mutations 2. Autoimmune disorders Mysthenia gravis Systemic lupus erythematous 3 Inflammatory disease Bronchial asthma Inflammattory bowel disease Pumonary inflammation 4 Viral infections Herpesviruses Poxviruses Adenoviruses Baculovirus Cowpox Disorders where apoptosis is excessive increase in cell death (Means hyperactive apoptosis). 1 AIDS CD4+ cells T- lymphocytes 2. Neurodegenerative disorders Alzheimer’s disease Epilepsy Parkinson’s disease Amyotrophic lateral sclerosis Retinitis pigmentosa Cerebellar degeneration Role of Caspases in Alzheimer's Disease a e Role of Caspases in HUNTINGTON DISEASE O g 3 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.