Pseudoapoptosis

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Pseudoapoptosis can be defined from multiple viewpoints, with an underlying premise of the differences in cellular processes and states relating to apoptosis. Pseudoapoptosis can be referred to as an apoptotic-like cellular state that can be readily reversed, [1] or as a process that induces rapid apoptosis through the introduction of drugs such as bleomycin. [2]

Apoptosis programmed cell death process

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between the ages of 8 to 14 year old approximately 20 to 30 billion cells die per day.

Contents

Pseudoapoptosis has been used to define a cellular state closely resembling the initial stages of apoptosis, but asserts a readily reversible state of which a cell can resume normal cellular function. Chemical and morphological changes a cell may undergo associated with pseudoapoptosis include blebbing, plasma membrane lipid asymmetry, cytoskeleton alterations, changes in mitochondrial function, and increased concentration of cytosolic calcium. Regardless of these cellular alterations, pseudoapoptotic cells reverse these changes to resume normal cellular process. [1]

Morphology (biology) In biology, the form and structure of organisms

Morphology is a branch of biology dealing with the study of the form and structure of organisms and their specific structural features.

Bleb (cell biology) irregular bulge in the plasma membrane

In cell biology, a bleb is a bulge or protrusion of the plasma membrane of a cell, human bioparticulate or abscess with an internal environment similar to that of a simple cell, characterized by a spherical, bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the internal structure of the cell, allowing the flexibility required to allow the cell to separate into individual bulges or pockets of the intercellular matrix. Most commonly, blebs are seen in apoptosis but are also seen in other non-apoptotic functions. Blebbing, or zeiosis, is the formation of blebs.

Cell membrane Biological membrane that separates the interior of a cell from its outside environment

The cell membrane is a biological membrane that separates the interior of all cells from the outside environment which protects the cell from its environment consisting of a lipid bilayer with embedded proteins. The cell membrane controls the movement of substances in and out of cells and organelles. In this way, it is selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall, the carbohydrate layer called the glycocalyx, and the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.

Pseudoapoptosis has also been used in some instances when describing an accelerated, drug induced apoptotic pathway by bleomycin. Cell death occurs as it would in apoptosis, but certain apoptotic mechanisms are not utilized when in the presence of bleomycin. [3] [4]

Bleomycin pharmaceutical drug, mixture of Bleomycin A2, and B2

Bleomycin is a medication used to treat cancer. This includes Hodgkin's lymphoma, non-Hodgkin's lymphoma, testicular cancer, ovarian cancer, and cervical cancer among others. Typically used with other cancer medications, it can be given intravenously, by injection into a muscle or under the skin. It may also be administered inside the chest to help prevent the recurrence of a fluid around the lung due to cancer; however talc is better for this.

Cell death biological processes that result in permanent cessation of all vital functions of a cell

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

Bleomycin

Bleomycin (BLM) is a cytotoxic, anticancerous drug that catalyzes double-stranded breaks (DSB) and single-stranded breaks (SSB) along DNA molecules. BLM has four distinguishable molecular components that determine function, including a DNA-binding region, metal binding domain, linker region, and a carbohydrate moiety. The metal binding domain associates with metals such as iron, cobalt, and zinc, each provides the basis of selectivity towards interaction with specific regions of DNA for catalytic cleavage. It is believed that the catalytic activity of BLM is carried out by associating with DNA molecules in linker regions between nucleosomes. Specific nucleotide sequences within the minor groove of a DNA molecule are a primary target as a catalytic site. [2]

DNA repair Processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

Iron Chemical element with atomic number 26

Iron is a chemical element with symbol Fe and atomic number 26. It is a metal, that belongs to the first transition series and group 8 of the periodic table. It is by mass the most common element on Earth, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust.

Cobalt Chemical element with atomic number 27

Cobalt is a chemical element with symbol Co and atomic number 27. Like nickel, cobalt is found in the Earth's crust only in chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal.

At appropriate dosages, BLM generates morphological changes resembling typical apoptotic events, such as membrane blebbing and altered mitochondrial functioning. Degradation of DNA is also induced without the presence or assistance of specific endonuclease or protease that are involved under classic apoptotic conditions, which defines the usage of this form of pseudoapoptosis. [4] The relative dose administered determines the extent to which DNA fragmentation occurs. In the presence of large BLM concentrations, pseudoapoptosis is observed as rapid DNA fragmentation occurs, resulting in cell death in the absence of typical apoptotic components such as specific endonucleases and proteases. [4] Experimental evidence has suggested that every BLM molecule induces an average of 8 to 10 DNA strand breaks. An average ratio of 6 single-stranded breaks are generated for every double-stranded break. These numbers are dependent upon the form of BLM taken into consideration as deglyco-bleomycin has been found to be 100 times less toxic than wild-type BLM. Other forms of BLM forming complexes with various metals has suggested other variability when inducing pseudoapoptosis. [3]

Endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain. Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically, while many, typically called restriction endonucleases or restriction enzymes, cleave only at very specific nucleotide sequences. Endonucleases differ from exonucleases, which cleave the ends of recognition sequences instead of the middle (endo) portion. Some enzymes known as "exo-endonucleases", however, are not limited to either nuclease function, displaying qualities that are both endo- and exo-like. Evidence suggests that endonuclease activity experiences a lag compared to exonuclease activity.

Protease enzyme, type of hydrolase

A protease is an enzyme that helps proteolysis: protein catabolism by hydrolysis of peptide bonds. Proteases have evolved multiple times, and different classes of protease can perform the same reaction by completely different catalytic mechanisms. Proteases can be found in all forms of life and viruses.

ATP-gated P2X7 receptors


Studies have shown to induce apoptotic-like cellular states through the activation of ATP-gated P2X7 receptors, but under certain conditions these changes are reversed and normal cellular functions continue. This process has also been used to define pseudoapoptosis. [5]

Antigen-presenting cells contain membrane bound P2X7 receptors which are involved in acute inflammatory responses. P2X purinergic receptors are ATP-gated ion channels that become activated in the presence of extracellular adenosine triphosphate (ATP). Prolonged exposure to extracellular ATP can generate or couple to a variety of cellular responses, including cell fusion, cell proliferation, release of pro-inflammatory cytokines, and bone formation. [5]

When pertaining to apoptosis, prolonged activation of P2X7 receptors can stimulate stress responses resulting in activated kinases responsible for inducing morphological and chemical changes, leading to apoptotic events and subsequent cellular death. Experimental deduction has shown when cells are briefly exposed to high extracellular ATP on the order of seconds to minutes, pseudoapoptotic events will occur. Apoptotic events such as membrane blebbing, phosphatidylserine flips (exposure to extracellular space), mitochondrial swelling, and microvesicle shedding are present, but cellular death does not occur. All of these events have proven to be fully reversible. Sustained activation for a longer period of time leads to further mitochondrial swelling, resulting in the release of cytochrome c, which initiates a cascade of apoptotic events leading to cellular death. [5]

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Signal transduction The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light),

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events as a signaling pathway.

Caspase family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death and inflammation. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 11 or 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

Fas ligand protein-coding gene in the species Homo sapiens

Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

Glyceraldehyde 3-phosphate dehydrogenase protein-coding gene in the species Homo sapiens

Glyceraldehyde 3-phosphate dehydrogenase is an enzyme of ~37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long established metabolic function, GAPDH has recently been implicated in several non-metabolic processes, including transcription activation, initiation of apoptosis, ER to Golgi vesicle shuttling, and fast axonal, or axoplasmic transport. In sperm, a testis-specific isoenzyme GAPDHS is expressed.

Phospholipid scramblase

Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are not members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases, flippases, and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet, facing the inside of the cell, contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme, present in the cell membrane, that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet, and vice versa.

Casein kinase 2 (CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumorigenesis as a potential protection mechanism for mutated cells. Proper CK2 function is necessary for survival of cells as no knockout models have been successfully generated.

Apoptosis-inducing factor

Apoptosis inducing factor is involved in initiating a caspase-independent pathway of apoptosis by causing DNA fragmentation and chromatin condensation. Apoptosis inducing factor is a flavoprotein. It also acts as an NADH oxidase. Another AIF function is to regulate the permeability of the mitochondrial membrane upon apoptosis. Normally it is found behind the outer membrane of the mitochondria and is therefore secluded from the nucleus. However, when the mitochondrion is damaged, it moves to the cytosol and to the nucleus. Inactivation of AIF leads to resistance of embryonic stem cells to death following the withdrawal of growth factors indicating that it is involved in apoptosis.

BH3 interacting-domain death agonist protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<i>Staphylococcus aureus</i> alpha toxin

Alpha-toxin, also known as alpha-hemolysin (Hla), is the major cytotoxic agent released by bacterium Staphylococcus aureus and the first identified member of the pore forming beta-barrel toxin family. This toxin consists mostly of beta-sheets (68%) with only about 10% alpha-helices. The hla gene on the S. aureus chromosome encodes the 293 residue protein monomer, which forms heptameric units on the cellular membrane to form a complete beta-barrel pore. This structure allows the toxin to perform its major function, development of pores in the cellular membrane, eventually causing cell death.

DAP3 protein-coding gene in the species Homo sapiens

28S ribosomal protein S29, mitochondrial, also known as death-associated protein 3 (DAP3), is a protein that in humans is encoded by the DAP3 gene on chromosome 1. This gene encodes a 28S subunit protein of the mitochondrial ribosome (mitoribosome) and plays key roles in translation, cellular respiration, and apoptosis. Moreover, DAP3 is associated with cancer development, but has been observed to aid some cancers while suppressing others.

DNAJC3 protein-coding gene in the species Homo sapiens

DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the DNAJC3 gene.

ENDOG protein-coding gene in the species Homo sapiens

Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene. This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress. As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson’s disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.

An Error has occurred retrieving Wikidata item for infobox ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.

Apoptosis is a programmed form of cell death involving the degradation of cellular constituents by a group of cysteine proteases called caspases. The caspases can be activated through either the intrinsic or extrinsic apoptotic pathways.

Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the Endoplasmic Reticulum and Golgi, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. Stage two the reversibility threshold for the cell is passed and it becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response.

Apoptotic-cell associated molecular patterns (ACAMPs) are molecular markers present on cells which are going through apoptosis, i.e. programmed cell death. The term was used for the first time by C. D. Gregory in 2000. Recognition of these patterns by the pattern recognition receptors (PRRs) of phagocytes then leads to phagocytosis of the apoptotic cell. These patterns include eat-me signals on the apoptotic cells, loss of don’t-eat-me signals on viable cells and come-get-me signals ) secreted by the apoptotic cells in order to attract phagocytes. Thanks to these markers, apoptotic cells, unlike necrotic cells, do not trigger the unwanted immune response.

Necroptosis

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding defense pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

An Error has occurred retrieving Wikidata item for infobox ADP/ATP translocase 2 is a protein that in humans is encoded by the SLC25A5 gene on the X chromosome.

Paraptosis

Paraptosis is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.

References

  1. 1 2 Annmarie Surprenant, et al. "Pseudoapoptosis Induced By Brief Activation Of ATP-Gated P2X7 Receptors." Journal of Biological Chemistry 280.40 (2005): 33968-33976
  2. 1 2 Vorobjev, Pavel, Olessia Tchaika, and Valentina Zarytova. "Efficient Cleavage Of DS DNA By Bleomycin Conjugated Via Hexaethylene Glycol Linker To Triplex-Forming Oligonucleotides." Nucleosides, Nucleotides & Nucleic Acids 23.6/7 (2004): 1047-1051.
  3. 1 2 L M Mir, et al. "The Ratio Of Single- To Double-Strand DNA Breaks And Their Absolute Values Determine Cell Death Pathway." British Journal of Cancer 84.9 (2001): 1272
  4. 1 2 3 L M Mir, et al. "In Vivo Evolution Of Tumour Cells After The Generation Of Double-Strand DNA Breaks." British Journal of Cancer 88.11 (2003): 1763.
  5. 1 2 3 Annmarie Surprenant, et al. "Pseudoapoptosis Induced By Brief Activation Of ATP-Gated P2X7 Receptors." Journal of Biological Chemistry 280.40 (2005): 33968-33976.
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