Apoptosis: (programmed cell death)


Entrance Test MCQ Topic


Apoptosis
Apoptosis can be defined as 'gene-directed cellular self-destruction'; it is sometimes referred to as 'programmed cell death' although this is really a phenomenon where cells are programmed to die at a particular point, e.g. during embryonic development, and even here cells may go through an apoptotic pathway. However, apoptosis is certainly a distinct process from other forms of oncosis leading to necrosis.



Apoptosis

Apoptosis, or programmed cell death, is a normal component of the development and health of multicellular organisms. Cells die in response to a variety of stimuli and during apoptosis they do so in a controlled, regulated fashion. This makes apoptosis distinct from another form of cell death called necrosis in which uncontrolled cell death leads to lysis of cells, inflammatory responses and, potentially, to serious health problems. Apoptosis, by contrast, is a process in which cells play an active role in their own death (which is why apoptosis is often referred to as cell suicide).

Upon receiving specific signals instructing the cells to undergo apoptosis a number of distinctive changes occur in the cell. A family of proteins known as caspases are typically activated in the early stages of apoptosis. These proteins breakdown or cleave key cellular components that are required for normal cellular function including structural proteins in the cytoskeleton and nuclear proteins such as DNA repair enzymes. The caspases can also activate other degradative enzymes such as DNases, which begin to cleave the DNA in the nucleus.

Apoptotic cells display distinctive morphology during the apoptotic process. This can be seen in the image below which shows a trophoblast cell undergoing apoptosis.

Typically, the cell begins to shrink following the cleavage of lamins and actin filaments in the cytoskeleton (A). The breakdown of chromatin in the nucleus often leads to nuclear condensation and in many cases the nuclei of apoptotic cells take on a "horse-shoe" like appearance (B). Cells continue to shrink (C), packaging themselves into a form that allows for their removal by macrophages. These phagocytic cells are responsible for clearing the apoptotic cells from tissues in a clean and tidy fashion that avoids many of the problems associated with necrotic cell death. In order to promote their phagocytosis by macrophages, apoptotic cells often ungergo plasma membrane changes that trigger the macrophage response. One such change is the translocation of phosphatidylserine from the inside of the cell to the outer surface. The end stages of apoptosis are often characterised by the appearance of membrane blebs (D) or blisters process. Small vesicles called apoptotic bodies are also sometimes observed (D, arrow).
There are a number of mechanisms through which apoptosis can be induced in cells. The sensitivity of cells to any of these stimuli can vary depending on a number of factors such as the expression of pro- and anti-apoptotic proteins (eg. the Bcl-2 proteins or the Inhibitor of Apoptosis Proteins), the severity of the stimulus and the stage of the cell cycle. Some of the major stimuli that can induce apoptosis are outlined in the illustration below.


In some cases the apoptotic stimuli comprise extrinsic signals such as the binding of death inducing ligands to cell surface receptors called death receptors. These ligands can either be soluble factors or can be expressed on the surface of cells such as cytotoxic T lymphocytes. The latter occurs when T-cells recognise damaged or virus infected cells and initiate apoptosis in order to prevent damaged cells from becoming neoplastic (cancerous) or virus-infected cells from spreading the infection. Apoptosis can also be induced by cytotoxic T-lymphocytes using the enzyme granzyme.

In other cases apoptosis can be initiated following intrinsic signals that are produced following cellular stress. Cellular stress may occur from exposure to radiation or chemicals or to viral infection. It might also be a consequence of growth factor deprivation or oxidative stress caused by free radicals. In general intrinsic signals initiate apoptosis via the involvement of the mitochondria. The relative ratios of the various bcl-2 proteins can often determine how much cellular stress is necessary to induce apoptosis.


The following represents a simplified model of extrinsic and intrinsic mechanisms and pathways that promote apoptosis in hen granulosa cells.



Simplified model of pro- and anti-apoptotic pathways in hen granulosa cells. Apoptotic cell death can be initiated by either an intrinsic or extrinsic pathway, both of which converge at the activation of caspase-3. Activation of this executioner enzyme is irreversible, and results in the cleavage of numerous structural and functional proteins (e.g., PARP) and the internucleosomal cleavage of genomic DNA. Cell death pathways are opposed by anti-apoptotic proteins that protect mitochondrial membrane integrity (Bcl-x, Bcl-2), block caspase activity (IAPs) or prevent signaling via death receptors (the adaptor protein, FLIP).

Expression of these anti-apoptotic proteins is regulated by gonadotropins (FSH and LH) and locally produced growth factors (IGF-I and EGF family ligands) via cell survival signaling pathways. The absence of sufficient anti-apoptotic protein expression (dotted green lines) is proposed to tip the balance in favor of activating pro-apoptotic pathways (solid red lines). Abbreviations: aCasp.-3, -7, -8, activated caspases; Apaf-1, Apoptosis Protease Activating Factor-1; Bid and tBid, intact or truncated BH3 Interacting Domain death agonist; cytC, cytochrome C; DD, death domain; DED, death effector domain; EGF, epidermal growth factor; FADD, Fas-Associated Death Domain; FLIP, Flice-like inhibitory protein; FSH, follicle-stimulating hormone; Inhibitor of Apoptosis Protein, IAP; IGF-I, insulin-like growth factor I; LH, luteinizing hormone; PARP, Poly-(ADP-ribose)-polymerase; PKA/cAMP, protein kinase A/cyclic AMP signaling pathway; PKB/Akt, protein kinase B/Akt signaling pathway. Each of the proteins and cell signaling pathways depicted has been characterized in hen granulosa cells, in vitro. For a more complete description with citations.
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http://www.sgul.ac.uk/depts/immunolo.../apoptosis.pdf
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