Programmed Cell Death - BIO201 Fall24

PROGRAMMED CELL DEATH Radhika Bhardwaj, PhD Department of Biotechnology, AIU R Bhardwaj_BIO 201 Outline: - Programmed c ell death or Apoptosis - Importance of Apoptosis - Pathways of Apoptosis Animal development : Begins with the which then differentiate rapid prol...

PROGRAMMED CELL DEATH Radhika Bhardwaj, PhD Department of Biotechnology, AIU R Bhardwaj_BIO 201 Outline: - Programmed c ell death or Apoptosis - Importance of Apoptosis - Pathways of Apoptosis Animal development : Begins with the which then differentiate rapid proliferation to produce the many that make up adult of embryonic cells specialized types of cells tissues and organs humans possess a total of approximately 1014 cells, consisting of more than 200 differentiated c ell types Starting from only a single cell-the fertilized egg- all the diverse cell types of the body are produced and organized into tissues and organs The complex process of development involves not only cell proliferation and differentiation but also cell death Cell death and Cell proliferation are balanced throughout the life of multicellular organisms  Cells die By a normal physiologic al process of programmed cell As a result of unpredictable death, which plays a key traumatic events, such as role both in embryonic development and in adult exposure to toxic chemicals tissues. Abnormalities of cell death are associated with a wide variety of illnesses: including c ancer, autoimmune disease, neurodegenerative disorders, such asParkinson'sand Alzheimer'sdisease.  Cell renewal In adult organisms, cell death must be balanced by cell renewal, and most tissues contain stem cells that are able to replace cells that have been lost. The ability of stem cells to proliferate and differentiate into a wide variety of cell types has generated enormous interest in the possible use of these cells, particularly embryonic stem cells, to replac e damaged tissues.  Programmed cell death or Apoptosis ▪ Programmed cell death is an active process, which usually proceeds by a distinct series of cellular changes in a cell and lead to its death known as apoptosis (first desc ribed in 1972) Occurs as a normal and controlled part of an organism’s growth or development The body uses to get rid of unneeded or abnormal cells ▪ The term apoptosis is derived from the Greek word describing the falling of leaves from a tree or petals from a flower ▪ Coined to differentiate this form of programmed cell death from the accidental cell deaths caused by inflammation or injury Apoptosis takes place starting from early development to adult stage for the homeostasis of multicellular organisms, during disease development and in response to different stimuli in many different systems  During apoptosis c hromosomal DNA is usually fragmented, the chromatin c ondenses, the nuc leus breaks up the c ell shrinks and breaks into apoptotic bodies. (A) Diagrammatic representation of the events of apoptosis. (B) Light micrographs of normal and apoptotic human leukemia cells illustrating chromatin condensation and nuclear fragmentation. (B, courtesy of D. R. Green/La Jolla Institute for Allergy and Immunology; C, courtesy of Ken Adams, Boston University.)  APOPTOSIS Neighboring cells remain healthy Apoptotic cell death usually does not lead to an inflammatory response APOPTOSIS—ACTIVE SUICIDE—TYPICALLY AFFECTS SINGLE CELLS Necrosis Necrosis usually results from irreversible injury to cells. Typically, groups of cells are affected. In most cases, necrotic cell death leads to an inflammatory response (red “activated” macrophages). Apoptotic c ells and c ell fragments are efficiently recognized and phagocytosed by both macrophages and neighboring cells, so cells that die by apoptosis are rapidly removed from tissues. In c ontrast, cells that die as a result of acute injury swell and lyse, releasing their contents into the extracellular space and causing inflammation Programmed Cell Death Versus Accidental Cell Death: Apoptosis Versus Necrosis Apoptosis, the most Necrosis, also called accidental cell widely studied pathway death, occurs when cells sustain a for programmed cell structural or chemical insult that death, is cellular suicide causes the cells to swell and resulting from activation undergo membrane lysis (Examples of a dedicated of such insults include extremes of intracellular program temperature and physical trauma) The removal of apoptotic cells is mediated by the expression of so-called "eat me" signals on the c ell surfac e. These signals include Phosphatidylserine (Phospholipid; a component of the cell membrane), which is normally restricted to the inner leaflet of the plasma membrane. During apoptosis, phosphatidylserine becomes expressed on the cell surface where it is recognized by receptors expressed by phagocytic cells. Programmed cell death: - responsible for balancing cell proliferation and maintaining constant cell numbers in tissues undergoing cell turnover. -In addition, programmed cell death provides a defense mechanism by which damaged and potentially dangerous cells can be eliminated for the good of the organism as a whole. Programmed c ell death / Apoptosis: - Apoptosis is valid for most of our cells except the Cancer cells. - As we know the life span of RBC is 120 days , after their turn is over, they need to be destroyed. The worn our RBCs are destroyed in spleen and obey Apoptosis. - Same phenomenon goes with other cells of our bodies like platelets , old WBC 's etc. Virus-infected c ells frequently undergo programmed cell death, thereby preventing the production of new virus partic les and limiting spread of the virus through the host organism. ▪ Other types of cellular insults (cause of cellular injury), such as DNA damage, also induce programmed cell death. ▪ In the c ase of DNA damage, programmed c ell death may eliminate cells carrying potentially harmful mutations, including cells with mutations that might lead to the development of ca ncer. Another well characterized example of programmed cell death is provided by development of the mammalian nervous system. Neurons are produced in excess, and up to 50% of developing neurons are eliminated by programmed c ell death. Those that survive are selected for having made the correct connections with their target cells, which secrete growth factors that signal cell survival by blocking the neuronal cell death program. The survival of many other types of cells in animals is similarly dependent on: - growth factors or - contacts with neighboring cells or - the extracellular matrix so programmed cell death is thought to play an important role in regulating the associations between c ells in tissues  Signals and Pathways of Apoptosis Two principal pathways lead to cell death by apoptosis. The intrinsic pathway The extrinsic pathway  The intrinsic pathway The extrinsic pathway Activated by internal surveillance Signals from other cells are the mechanisms or signals sent (or not sent) primary triggers by other cells. Direct contact of a killer cell with Signals that induce this pathway include the target cell activates specific DNA damage, exposure to chemicals receptors that initiate this that interfere with cellular pathways and pathway, starting at the plasma excessive activation of factors that membrane. promote cell-cycle progression.  The intrinsic pathway The extrinsic pathway Withdrawal of nutrients or survival This pathway is also widely used to signals from the environment also control cell populations in the activates the intrinsic pathway. immune system. Activation of the extrinsic pathway is one strategy that Survival signals include cytotoxic T lymphocytes use to kill -lymphokines, such as interleukin-2 and cells that are recognized as foreign 3, essential for survival of (or as harboring foreign pathogens). thymocytes; -Nerve growth factor- required for In many cells, the extrinsic pathway survival of many neurons; and activates the intrinsic pathway, -extracellular matrix- required for which is then responsible for killing survival of epithelial cells. the cell Central Regulators of Apoptosis: The Bcl-2 Family The Bcl-2 family of proteins is divided into 3 functional groups. Antiapoptotic proteins (e.g., Bcl-2 and Bcl-xL) have four Bcl-2 homology domains (BH1-BH4) The multidomain proapoptotic (e.g., Bax and Bak) have three homology domains (BH1- BH3), BH3-only proapoptotic protein(e.g., Bid, Bad, Noxa, Puma, and Bim) have only one homology domain (BH3). In healthy cells: Bak is loosely associated with the mitochondrial outer membrane, and Bax is in the cytoplasm In mammals, two of the killer proteins, Bax and Bak, are essential for activation of the intrinsic pathway  Intrinsic pathway Antiapoptotic molecules Proapoptotic signal molecules (BCl2 and BCl-xl) (BAX, BAK) When active, When act on Mitochondria, inhibit Mitochondria, promote Apoptosis and Cytochrome C is released and thereby Caspases which lead to no Cyt C released, cell death no Caspases leads to Programmed Cell Death prevent Apoptosis Binding of antiapoptotic Bcl-2 family members to Bax/Bak prevents mitochondrial outer membrane permeabilization.  BH3-only family members can either directly indirectly promote death promote death by by facilitating Bax/Bak binding and neutralizing oligomerization antiapoptotic Bcl-2 family members. In the cytoplasm, cytochrome c binds to the scaffolding protein Apaf-1, a mammalian homolog of C. elegans CED-4 protein, causing it to undergo a conformational change that exposes a hidden bound adenosine diphosphate (ADP) to solvent. Exchange of this ADP for deoxyadenosine triphosphate (dATP) allows Apaf-1 to form a wheel-like structure with seven spokes called the apoptosome. Apaf-1 in the apoptosome binds caspase 9 through an N-terminal caspase recruitment domain Binding to the apoptosome elevates the catalytic activity of procaspase 9 approximately 2000-fold without the need for its cleavage. Thus, the active form of caspase 9 is an oligomeric complex of the procaspase with the apoptosome. Activated caspase 9 then cleaves multiple procaspase 3 zymogens, amplifying the cell death cascade. It also cleaves itself, triggering its release from the apoptosome with a resulting loss of activity. This autocleavage acts like a timer limiting apoptosome activity Extrinsic pathway Extrinsic pathway FasL TNF –Alpha Fas TNF-R or Extrinsic pathway CTC (Cytotoxic T cells) Release Granyme B, perforate membranes, Perforins, Caspases , cell death  EXTRINSIC CELL DEATH PATHWAY. The pathways shown are downstream of the Fas cell death receptor A. Preligation. B.Ligand docked on a trimerized receptor. C. Release of active caspase. D. Activation of effector caspases. E.Activation of the intrinsic death pathway. F. Death DISC: death-inducing signaling complex; FADD, Fas-associated death domain Extrinsic Pathway of Apoptotic Death Cells Protein ligands on the express surface of other cells bind and activate these receptors, turning on pathways that can lead to apoptotic death at least six different cell surface molecules, collectively termed death receptors, that can trigger apoptotic death. The Fas ligand (a trimeric 40-kD intrinsic membrane protein found on the surface of cells). Cytotoxic T lymphocytes use Fas ligand to rid the body of virally infected cells. When a cytotoxic T lymphocyte contacts a target cell, the Fas ligand on the lymphocyte surface binds to Fas on the target cell and initiates the extrinsic pathway of apoptotic death Ligand binding activates signaling from the intracellular death domain of Fas, possibly by stabilizing Fas trimers or by altering their conformation. Activated Fas binds an adapter protein called FADD (Fas-associated protein with a death domain), assembling the DISC. The DISC is an activation platform that binds procaspase 8 through interactions involving another type of motif called the death effector domain, which is present on both FADD and the prodomain of procaspase 8. Procaspase 8 monomers dimerize on the DISC and acquire catalytic activity. These dimers can cleave neighboring dimers, creating and releasing heterotetrameric active caspase 8, which can initiate the caspase cascade by activating downstream effector caspases. Frequently, caspase 8 cleaves the BH3- only protein Bid, thereby activating the intrinsic death pathway Common causes of programmed cell death: Developmentally Defective Cells Excess Cells Cells That Serve No Function Cells With Perturbed Cell Cycles Virus-Infected Cell Chemotherapeutic Killing of Cells Apoptosis - Introduction, Morphologic Changes and Mechanism - YouTube Necrosis vs. Apoptosis: Cell Death - YouTube Apoptosis (Intrinsic, Extrinsic Pathways) vs. Necrosis – YouTube p53 Tumour Suppressor (2016) by Etsuko Uno wehi.tv - YouTube