Apoptosis and Cell Necrosis

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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: Cell death by injury (NECROSIS) - Mechanical damage -Exposure to toxic chemicals -Lack of Oxygen -Extremes of temperature Cell death by suicide (APOPTOSIS) -Internal signals -External signals

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Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmi c proteins. The process was recognized in 1972 by the distinctive morphologic appearance of membrane-bound fragments derived from cells. Apoptosis derived from Greek “ apo ,” meaning “away from,” and “ptosis,” meaning “to droop” or “to fall.”

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Apoptosis occurs normally both during development and throughout adulthood, and serves to eliminate unwanted, aged or potentially harmful cells. It is also a pathologic event when diseased cells become damaged beyond repair and are eliminated. Apoptosis in Physiologic Situations The programmed destruction of cells during embryogenesis, including implantation, organogenesis, developmental involution, and metamorphosis. Involution of hormone-dependent tissues upon hormone withdrawal ,

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Cell loss in proliferating cell populations, to maintain their constant number (homeostasis). Elimination of potentially harmful self-reactive lymphocytes, either before or after they have completed their maturation Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response

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Development of toes Incomplete apoptosis

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Apoptosis in Pathologic Conditions DNA damage. Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly or via production of free radicals. These injurious stimuli can cause apoptosis if the insult is mild, but larger doses of the same stimuli may result in necrotic cell death. Accumulation of misfolded proteins. Excessive accumulation of misfolded proteins in the ER leads to a condition called ER stress, which culminates in apoptotic cell death. Pathologic atrophy in parenchymal organs after duct obstruction, such as occurs in the pancreas, parotid gland, and kidney.

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Cell death in certain infections, particularly viral infections, in which loss of infected cells is largely due to apoptosis that may be induced by the virus (as in adenovirus and HIV infections) or by the host immune response (as in viral hepatitis).

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Cell shrinkage. The cell is smaller in size; the cytoplasm is dense and the organelles are more tightly packed. Chromatin condensation. The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments. Formation of cytoplasmic blebs and apoptotic bodies. The apoptotic cell first shows extensive surface blebbing , then undergoes fragmentation into membrane-bound apoptotic bodies

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DNA and Protein Breakdown Apoptotic cells exhibit a characteristic breakdown of DNA into large 50- to 300-kilobase pieces.Subsequently , there is cleavage of DNA by Ca 2+ - and Mg 2+ -dependent endonucleases into fragments whose sizes are multiples of 180 to 200 base pairs. The fragments may be visualized by electrophoresis as DNA “ladders”. Membrane Alterations and Recognition by Phagocytes . The plasma membrane of apoptotic cells changes in ways that promote the recognition of the dead cells by phagocytes. One of these changes is the movement of some phospholipids (notably phosphatidylserine ) from the inner leaflet to the outer leaflet of the membrane.

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Apoptosis of an epidermal cell in an immune reaction. The cell is reduced in size and contains brightly eosinophilic cytoplasm and a condensed nucleus. B, This electron micrograph of cultured cells undergoing apoptosis shows some nuclei with peripheral crescents of compacted chromatin, and others that are uniformly dense or fragmented

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Withdrawal of positive signals The survival of most cells requires that they receive continuous stimulation from other cells. Some examples of positive signals: growth factors for neurons Interleukin-2 (IL-2), an essential factor for the mitosis of lymphocytes.

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Receipt of negative signals increased levels of oxidants within the cell damage to DNA by these oxidants or other agents like ultraviolet light x-rays chemotherapeutic drugs accumulation of proteins that failed to fold properly into their proper tertiary structure molecules that bind to specific receptors on the cell surface and signal the cell to begin the apoptosis program. These death activators include: Tumor necrosis factor-alpha(TNF-α) that binds to the TNF receptor; Lymphotoxin (also known as TNF-β) that also binds to the TNF receptor; Fas ligand( FasL ), a molecule that binds to a cell-surface receptor named Fas(also called CD95).

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A specific feature of apoptosis is the activation of several members of a family of cysteine proteases named caspases . T he “c” refers to a cysteine protease (i.e., an enzyme with cysteine in its active site), and “ aspase ” refers to the unique ability of these enzymes to cleave after aspartic acid residues. Expressed as zymogens ( procaspases ) that have three domains: an N-terminal prodomain that is proteolytically excised on activation, followed by sequences comprising the active enzyme’s αandβsubunits that are proteolytically separated on activation . The presence of cleaved, active caspases is a marker for cells undergoing apoptosis

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Caspase activation

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As of November 2009, twelve caspases have been identified in humans. two types of apoptotic caspases : initiator (apical) caspases and effector (executioner) caspases . Initiator caspases (e.g., CASP2 , CASP8 , CASP9 , and CASP10 ) cleave inactive pro-forms of effector caspases , thereby activating them. Caspase-9 & 2 contains caspase recruitment domain(CARD) that promotes the interaction with certain scaffolding and regulatory proteins Caspase-8 and-10 each contains DeathEffector Domains, through which they bind to DEDs on their target adaptor proteins Effector caspases (e.g., CASP3 , CASP6 , CASP7 ) in turn cleave other protein substrates within the cell, to trigger the apoptotic process.

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The process of apoptosis may be divided into an initiation phase, during which some caspases become catalytically active, and an execution phase, during which other caspases trigger the degradation of critical cellular components. Initiation of apoptosis occurs principally by signals from two distinct pathways: the intrinsic, or mitochondrial, pathway, and the extrinsic, or death receptor–initiated, pathway .

The Intrinsic (Mitochondrial) Pathway of Apoptosis:

The Intrinsic (Mitochondrial) Pathway of Apoptosis

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The intrinsic or mitochondrial pathway is the major mechanism of apoptosis in all mammalian cells. This pathway of apoptosis is the result of increased mitochondrial permeability and release of pro-apoptotic molecules (death inducers) into the cytoplasm The release of these mitochondrial proteins (mostly cytochrome c) is controlled by a finely orchestrated balance between pro- and anti-apoptotic members of the Bcl family of proteins. This family is named after Bcl-2 , which was identified as an oncogene in a B-cell lymphoma. There are more than 20 members of the Bcl family, and most of them function to regulate apoptosis.

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Classified into 3 groups Group I - Bcl-2 and Bcl -XL -C-terminal hydrophobic segments -anti-apoptotic Group II - Bax and Bak -lack BH4 region -pro-apoptotic Group III - Bad,Bid,Bik,Bim and Blk -possess only BH3 region - proapoptotic

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Growth factors and other survival signals stimulate production of anti-apoptotic proteins, the main ones being Bcl-2, Bcl -x. normally reside in the cytoplasm and in mitochondrial membranes control mitochondrial permeability and prevent leakage of mitochondrial proteins that have the ability to trigger cell death . When cells are deprived of survival signals or their DNA is damaged, or misfolded proteins induce ER stress, sensors of damage or stress are activated. These sensors are members of the Bcl family called Bim , Bid, and Bad that contain a single “Bcl-2 homology domain” (the third of the four such domains) and are called “BH3-only proteins.”

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They activate two critical ( proapoptotic ) effectors, Bax and Bak , which form oligomers that insert into the mitochondrial membrane and create channels that allow proteins from the inner mitochondrial membrane to leak out into the cytoplasm. BH3-only proteins may also bind to and block the function of Bcl-2 and Bcl -x and decline their synthesis too. The net result of Bax-Bak activation coupled with loss of the protective functions of the anti-apoptotic Bcl family members is the release into the cytoplasm of several mitochondrial proteins including cytochrome c that can activate the caspase cascade.

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Once released into the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosis-activating factor-1), which forms a wheel-like hexamer that has been called the apoptosom . This complex is able to bind caspase-9, the critical initiator caspase of the mitochondrial pathway, and the enzyme cleaves adjacent caspase-9 molecules, thus setting up an auto-amplification process. Other mitochondrial proteins, like Smac /DIABLO, enter the cytoplasm, where they bind to and neutralize cytoplasmic proteins that function as physiologic inhibitors of apoptosis (called IAPs). T he neutralization of these IAPs permits the initiation of a caspase cascade,which causes the apoptosis

The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis:

The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis

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This pathway is initiated by engagement of plasma membrane death receptors on a variety of cells. Death receptors are members of the TNF receptor family that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain . The best-known death receptors are the type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95). The mechanism of apoptosis induced by these death receptors is well illustrated by Fas. The ligand for Fas is called Fas ligand ( FasL ).

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When FasL binds to Fas, three or more molecules of Fas are brought together, and their cytoplasmic death domains form a binding site for an adapter protein that also contains a death domain and is called FADD ( F as- a ssociated d eath d omain). FADD that is attached to the death receptors in turn binds an inactive form of caspase-8 (and, in humans, caspase-10), again via a death domain to form DISC Multiple pro-caspase-8 molecules are thus brought into proximity, and they cleave one another to generate active caspase-8. The enzyme then triggers a cascade of caspase activation by cleaving and thereby activating other pro- caspases , and the active enzymes mediate the execution apoptosis

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Some cells produce intracellular blocking proteins such as cFLIP , which resembles an initiator procaspase but lacks the proteolytic domain ; it competes with procaspase 8 and 10 and thereby inhibits their activation. Certain herpes viruses and poxviruses encode v-FLIP that function similarly to c-FLIP to prevent apoptosis thereby permitting the virus to propagate in the infected cells .

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The BH-3 only protein Bid is the link between two pathways.When death receptor activate the extrinsic pathway initiator caspase cleaves Bid , producing t- Bid which translocates to mitochondria and inhibit anti-apoptotic Bcl-2.

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Inactivation of enzymes involved in DNA repair. The enzyme poly (ADP-ribose) polymerase, or PARP, is an important DNA repair enzyme.The ability of PARP to repair DNA damage is prevented following cleavage of PARP by caspase-3. Breakdown of structural nuclear proteins. Lamins are intra-nuclear proteins that maintain the shape of the nucleus and mediate interactions between chromatin and the nuclear membrane. Degradation of lamins by caspase 6 results in the chromatin condensation and nuclear fragmentation. Fragmentation of DNA. The fragmentation of DNA is caused by an enzyme known as CAD, or caspase activated DNase . Normally CAD exists as an inactive complex with ICAD (inhibitor of CAD). During apoptosis, ICAD is cleaved by caspases , such as caspase 3, to release CAD. Rapid fragmentation of the nuclear DNA follows.

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Plasma membrane blebs and the cell breaks up into several membrane spheres called “apoptotic bodies ”. Phagocytic Cells remove the “apoptotic bodies”

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Apoptosis inducing factor, a flavoprotein is involved in initiating a caspase -independent pathway of apoptosis. triggers chromatin condensation and DNA degradation in a cell in order to induce programmed cell death. The process triggering apoptosis starts when the mitochondria releases AIF, which exits through the mitochondrial membrane, enters the cytosol, and finally ends up in the cell nucleus where it signals the cell to condense its chromosomes and fragment its DNA molecules in order to prepare for cell death

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