Apoptosis

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A P O P T O S I S

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Introduction Discovery and Occurrence * Functions * Process - Cell termination - Pathways - Homeostasis - Mitochondrial regulation - Development - Removal of dead cells - Lymphocyte interactions Defective apoptotic pathways Regulation of apoptosis Dysregulation of p53 HIV progression Viral infection Apoptosis in plants * Caspase Independent Apoptosis INDEX 1

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For every cell, there is a time to live and a time to die. There are two ways in which cells die: Death by injury Death by suicide INTRODUCTION 2

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DEATH BY INJURY Cells are damaged by injury, such as by Mechanical damage Exposure to toxic chemicals Undergo a characteristic series of changes: They swell The cell contents leak out Inflammation 3

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Cell shrink. Develop bubble-like blebs on their surface. Chromatin in their nucleus degraded. Mitochondria break down with the release of cytochrome c . Break into small, membrane-wrapped, fragments. This "eat me" signal is bound by receptors on phagocytic cells like macrophages and dendritic cells which then engulf the cell fragments . The phagocytic cells secrete cytokines that inhibit inflammation. DEATH BY SUICIDE 4

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COMPACTION & SEGREGATION CONDANSATION OF CYTOPLASM NUCLEAR FRAGMENTATION BLEBBING CELL FRAGMENTATION PHAGOCYTOSIS APOPTOTIC BODY PHAGOCYTIC CELL 5

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WHAT IS APOPTOSIS? Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes, These changes includes… Blebbing, Loss of cell membrane, Cell shrinkage, Nuclear fragmentation, Chromatin condensation, chromosomal DNA fragmentation. 6

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Histologic cross section of embryonic foot of mouse (Mus musculus) in 15.5 day of its development. There are still cells between fingers. (Full development of mouse lasts 27 days.) For example, the differentiation of fingers and toes in a developing human Embryo occurs because cells between the fingers apoptose. Between 50 to 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 to 14, approximately 20 to 30 billion cells die a day. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight. Excessive apoptosis causes ATROPHY , such as in ISCHEMIC damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as CANCER . Histologic cross section of embryonic foot of mouse ( Mus musculus ) in 15 day of its development. There are still cells between fingers. (Full development of mouse lasts 27 days.) 7

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Formation of fingers and toes of fetus. In frogs – cells which has no longer needed such as amphibian tadpole tail during metamorphosis removed by apoptosis. Formation of proper connection between neurons in brain . Sloughing off the inner lining of the uterus at the start of menstruation. In the human body about 1,00,000 cells were produced by cell division in every second and a similar no. of cells die by apoptosis. Apoptosis in homeostasis of immune system : millions of B and T cells are generated every day and the majority (>95%) of those die during maturation. Removal of damaged cells – cells with damaged DNA that can not be repaired by appropriately usually removed by apoptosis. OCCURRENCE / NEED OF APOPTOSIS 9

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Cell termination Homeostasis Development Lymphocyte interactions FUNCTIONS 10

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CELL TERMINATION Apoptosis occurs when a cell is damaged , infected with a virus , or undergoing stressful conditions such as arsenic poisoning . Damage to DNA from ionizing radiation or toxic chemicals can also induce apoptosis via the actions of the tumor-suppressing gene p53 . The "decision" for apoptosis can come from the cell itself, from the surrounding tissue, or from a cell that is part of the immune system. Apoptosis also plays a role in preventing cancer. If a cell is unable to undergo apoptosis, it continues to divide and develop into a tumor . 11

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In the adult organism, the number of cells is kept relatively constant through cell death and division . Cells must be replaced when they malfunction or become diseased, but proliferation must be offset by cell death. Homeostasis is achieved when the rate of mitosis in the tissue is balanced by the rate of cell death. The cells divide faster than they die, resulting in the development of a tumor. The cells divide slower than they die, causing cell loss. HOMEOSTASIS 12

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DEVELOPMENT Programmed cell death is an integral part of both plant and animal tissue development. Development of an organ or tissue is often preceded by the extensive division and differentiation of a particular cell. During vertebrate embryo development, structures called the Notochord and the floor plate secrete a chemical of the signaling molecule which induces apoptosis. During development, apoptosis is tightly regulated and different tissues use different signals for inducing apoptosis. In birds, bone morphogenetic protein (BMP) signaling is used to induce apoptosis . In drosophila flies , steroid hormones regulate cell death. 13

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LYMPHOCYTES INTERACTION The development of B lymphocytes and T lymphocytes in a human body is a complex process that creates a large pool of diverse cells and subsequently eliminates those potentially damaging to the body. cytotoxic T cells are able to directly induce apoptosis by opening up pores in the target's membrane and releasing chemicals that bypass the normal apoptotic pathway. The pores are created by the action of secreted perforin , and the granules contain granzyme B , a serine protease that activates apoptotic pathway. 14

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PROCESS The process of apoptosis is controlled by either extracellularly or intracellularly . Extracellular signals - toxin, hormones, growth factors, cytokines . These signals may positively (i.e., trigger) or negatively (inhibit) affect apoptosis. A cell initiates intracellular apoptotic signaling in response to a stress, which may bring about cell suicide. For example, by damage to the membrane, can all trigger the release of intracellular apoptotic signals by a damaged cell . A number of cellular components, may also helps into the regulation of apoptosis . 15

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Apoptotic signals must cause regulatory proteins to initiate the apoptosis pathway. This step allows apoptotic signals to cause cell death, or the process to be stopped, should the cell no longer need to die. Several proteins are involved in the process of apoptosis. Another extrinsic pathway for initiation identified in several toxin studies is an increase in calcium concentration. 16

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PROCESS Pathways Mitochondrial regulation Removal of dead cells 17

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MITOCHONDRIAL REGULATION The mitochondria are essential to multicellular life , a cell ceases to respire aerobically and quickly dies, a fact exploited by some apoptotic pathways. Apoptotic proteins cause mitochondrial swelling through the formation of membrane pores may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out. Mitochondrial proteins known as SMACs (second mitochondria-derived activator of caspases) are released into the cytosol following an increase in permeability. SMAC binds to inhibitor of apoptosis protein (IAPs) and deactivates them, preventing the IAPs from arresting the apoptotic process and therefore allowing apoptosis to proceed. IAP also normally suppresses the activity of a group of cysteine protein called caspases , which carry out the degradation of the cell, therefore the actual degradation enzymes can be seen to be indirectly regulated by mitochondrial permeability. 19

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The nuclear envelope becomes discontinuous and the DNA inside it is fragmented in a process referred to as karyorrhexis . The nucleus breaks into several discrete chromatin bodies or nucleosomal units due to the degradation of DNA. The cell membrane shows irregular buds known as blebs . The cell breaks apart into several vesicles called apoptotic bodies , which are then phagocytosed. Apoptosis progresses quickly and its products are quickly removed, making it difficult to detect or visualize. During karyorrhexis, endonuclease enzyme activation leaves short DNA fragments, regularly spaced in size. These give a characteristic "laddered" appearance on agar gel after electrophoresis. Tests for DNA laddering differentiate apoptosis from ischemic or toxic cell death . 20

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REMOVAL OF DEAD CELLS The removal of dead cells by neighboring phagocytic cells has been termed efferocytosis. Dying cells that undergo the final stages of apoptosis display phagocytotic molecules, such as phosphatidylserine , on their cell surface. Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane , but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as scramblase. These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages. Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response. 21

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DEFECTIVE APOPTOTIC PATHWAYS The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood. In a living organism this can have disastrous effects, often in the form of disease or disorder. The normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell becoming cancerous or diseased. 22

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A recently-described example of this concept in action can be seen in the development of a lung cancer called NCI-H460 . The X-linked inhibitor of apoptosis protein ( XIAP ) is overexpressed in cells of the H460 cell line. XIAPs bind to the processed form of caspase-9, and suppress the activity of apoptotic activator cytochrome C , therefore overexpression leads to a decrease in the amount of pro-apoptotic agonists. As a consequence, the balance of anti-apoptotic and pro-apoptotic effectors is upset in favour of the former, and the damaged cells continue to replicate despite being directed to die. 23

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REGULATION OF APOPTOSIS Dysregulation in apoptosis may resulting cancer, autoimmune disorders. Anticancer drug induce apoptosis in susceptible cells. p53 - The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. Bcl 2 - It is involved in resistance to conventional cancer treatment. It prevents apoptosis and inhibits the caspases. Bak - The growth of cancer cells was significantly inhibited after Bak gene was transfected. Apoptotic cells were increased significantly. BTG - Expression in p53 dependent and independent cellular response to DNA damage. 24

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DYSREGULATION OF p53 The tumor-suppressor protein p53 accumulates when DNA is damaged due to a chain of biochemical factors. Induced transcription of the p53 gene and result in the increase of p53 protein level and enhancement of cancer cell-apoptosis . p53 prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. Any disruption to the regulation of the p53 or interferon genes will result in impaired apoptosis and the possible formation of tumors. 25

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HIV PROGRESSION The progression of the human immunodeficiency virus infection to AIDS is primarily due to the depletion of CD-4 + T-lymphocytes which leads to a compromised immune system. One of the mechanisms by which T-helper cells are depleted is apoptosis. HIV enzymes deactivate anti-apoptotic Bcl-2 This does not directly cause cell death. In parallel, these enzymes activate pro-apoptotic procaspase-8 , which does directly activate the mitochondrial events of apoptosis. HIV may increase the level of cellular proteins which prompt Fas-mediated apoptosis . HIV proteins decrease the amount of CD4 glycoprotein marker present on the cell membrane. 26

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Released viral particles and proteins present in extracellular fluid are able to induce apoptosis in nearby T helper cells. HIV decreases the production of molecules involved in marking the cell for apoptosis, giving the virus time to replicate and continue releasing apoptotic agents into the surrounding tissue. The infected CD4 + cell may also receive the death signal from a cytotoxic T cell. 27

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APOPTOSIS AND CANCER Several human papilloma viruses ( HPV ) have been implicated in causing cervical cancer. Epstein-Barr Virus ( EBV )associated with some lymphomas. Some B-cell leukemia & lymphoma express high levels of Bcl-2. Melanoma cells avoid apoptosis by inhibiting the expression of the gene encoding Apaf-1 . 28

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VIRAL INFECTION Viruses can trigger apoptosis of infected cells. Expression of viral proteins coupled to MHC proteins on the surface of the infected cell. It allowing recognition by cells of the immune system (such as Natural Killer and cytotoxic T cells) that then induce the infected cell to undergo apoptosis. Most viruses encode proteins that can inhibit apoptosis. These homologs can inhibit pro-apoptotic proteins such as BAX and BAK , which are essential for the activation of apoptosis. 29

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APOPTOSIS IN PLANTS Programmed cell death; in plants has a number of molecular similarities to animal apoptosis, but it also has differences, notably the presence of a cell wall and the lack of an immune system which removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuoles which ruptures as the cell dies. Whether this whole process resembles animal apoptosis closely enough to warrant using the name apoptosis (as opposed to the more general programmed cell death ) is unclear. 30

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CASPASE INDEPENDENT APOPTOSIS There is an extrinsic pathway that has been noticed in several toxicity studies. It was shown that an increase in calcium concentration within a cell , caused by drug activity, also has the ability to cause apoptosis via a calcium-binding calpain protease. 31