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The apoptosis mechanisms in a cell are like a type of 'self-destruction mechanism': is this correct?
As with any type of complex system with various necessary functions, if it has a set of self-destruction mechanisms for 'shutting down' the whole system, it would require some sort of 'internal programming' that can somehow 'target' each of the system's necessary functions and 'disrupt' each of them simultaneously or in some 'order'.
In other words a self-destruction system in order to be effective would have to be able to 'target' each necessary function in the system. And if a biological system has a mutation or a set of mutations that 'distort' some parts of the system then the self-destruct mechanisms might not be able to 'target' all of the functions.
So maybe the cellular mutation 'automatically' makes it hard or impossible for the self-destruct mechanisms to work. Is this possible??
Not at all. In order to self destruct, you don't need to disable all necessary functions, you just need to disable one. That's why the functions are called "essential". To take a very simple example, in every movie you've seen where the self destruct has been activated, that self destruct mechanism was almost certainly a bomb that blew the ship/installation/planet or whatever up. The self destruct did not go around disabling individual processes, it just activated a bomb and destroyed everything.
Apoptosis is quite similar. While there are many essential processes in a cell whose failure can activate apoptosis, the mechanism of apoptosis itself usually involves the straightforward destruction (lysis) of the cell. Simply put, the cell digests itself, breaking down its various constituent parts and, finally, destroying the cell membrane and breaking up the cell itself. For a summary see this Wikipedia page or here.
Briefly, when apoptosis is triggered, the caspase cascade is initialized which results in the breakdown of various proteins in the cell and, finally, in cell lysis. It really is analogous to setting of the bomb that destroys the facility of the bad guys.
Difference Between Autophagy and Apoptosis
Autophagy and apoptosis are self-degradative processes occurring naturally inside the cell, balancing the functioning of multicellular organisms during their lifetime. Autophagy helps the cell to survive under stressful conditions such as deficiency of nutrients. Apoptosis causes cell death due to either a physiological or pathological process. The main difference between autophagy and apoptosis is that apoptosis is a predefined cell suicide, where the cell actively destroys itself, maintaining a smooth functioning in the body whereas autophagy is a self-degradative process of its own components, balancing the sources of energy during development.
Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression
Activation-induced cell death is a general mechanism of immune homeostasis through negative regulation of clonal expansion of activated immune cells. This mechanism is involved in the maintenance of self- and transplant tolerance through polarization of the immune responses. The Fas/Fas-ligand interaction is a major common executioner of apoptosis in lymphocytes, with a dual role in regulatory T cell (Treg) function: Treg cell homeostasis and Treg cell-mediated suppression. Sensitivity to apoptosis and the patterns of Treg-cell death are of outmost importance in immune homeostasis that affects the equilibrium between cytolytic and suppressor forces in activation and termination of immune activity. Naive innate (naturally occurring) Treg cells present variable sensitivities to apoptosis, related to their turnover rates in tissue under steady state conditions. Following activation, Treg cells are less sensitive to apoptosis than cytotoxic effector subsets. Their susceptibility to apoptosis is influenced by cytokines within the inflammatory environment (primarily interleukin-2), the mode of antigenic stimulation and the proliferation rates. Here, we attempt to resolve some controversies surrounding the sensitivity of Treg cells to apoptosis under various experimental conditions, to delineate the function of cell death in regulation of immunity.
MECHANISMS OF APOPTOSIS THROUGH STRUCTURAL BIOLOGY
AbstractApoptosis plays a central role in the development and homeostasis of metazoans. Research in the past two decades has led to the identification of hundreds of genes that govern the initiation, execution, and regulation of apoptosis. An earlier focus on the genetic and cell biological characterization has now been complemented by systematic biochemical and structural investigation, giving rise to an unprecedented level of clarity in many aspects of apoptosis. In this review, we focus on the molecular mechanisms of apoptosis by synthesizing available biochemical and structural information. We discuss the mechanisms of ligand binding to death receptors, actions of the Bcl-2 family of proteins, and caspase activation, inhibition, and removal of inhibition. Although an emphasis is given to the mammalian pathways, a comparative analysis is applied to related mechanistic information in Drosophila and Caenorhabditis elegans.
Relation between cell apoptosis and diseases
As cellular apoptosis is one of the fundamental actions of how we survive, it can be linked to an innumerable amount of diseases. This is because the process of apoptosis works in a very complicated balance and is essentially sequential. Every part of the sequence needs to work properly for the cell death to be effective and safe. Certain cells, such as carcinogenic cancer cells, can disrupt this sequence. This can damage the cells. If the sequence is disrupted, a cell which was programmed to die will live and pass on its faulty genetics to other cells. In turn, this can lead to cancer development (metastasis). In certain types of cancers, chemical and radiation therapies are used for inducing the process of cell apoptosis.
It is not just a lack of apoptosis which can be damaging to humans. Too much occurrence of apoptosis can result in hyperactive apoptosis. This leads to too many cells dying and is linked to many neurological conditions. This is because the increased cell death destroys brain cells, something which is common in the degenerative diseases Parkinson's and Alzheimer's. HIV is a virus which can trigger hyper apoptosis and leads to a decreased immunity.
Other viruses can have an affect on apoptosis. They do so by a variety of mechanisms such as receptor binding or by expressing the proteins of the cell surface which protect it from disease. As you have probably worked out, it is a complicated process which is in a delicate balance. This is why we need to know what is apoptosis? Affecting it in an attempt to stop diseases from spreading is a similarly complicated process. This is why the strides we have made to do so have been so mind-blowingly incredible. Hopefully, more incredible improvements will occur as scientists and molecular biologists further understand processes like apoptosis.
If you want to read similar articles to What Is Cell Apoptosis?, we recommend you visit our University degrees category.
Extrinsic Pathway of Apoptosis (Apoptosis Molecular Mechanism Part 2)
In the extrinsic pathway of apoptosis, the death-inducing signal for the programmed cell death is triggered by an external stimulus. For receiving such an external death-inducing signal, the cell possesses plasma membrane receptors specific to each stimulus and thus the extrinsic signalling of apoptosis is also known as the Receptor Mediated programmed cell death pathway.
The external stimuli for the apoptosis in most of the cases will be a cytokine. The most studied cytokine to induce extrinsic pathway of apoptosis is an extracellular messenger protein called Tumor Necrosis Factor (TNF). TNF is so named because it was first discovered as a protein factor which induces cell death in cancerous cells. The TNF cytokine is produced by the cells of the immune system in response towards the adverse conditions. The adverse conditions that can provoke the immune cells to produce TNF are:
Ø Introduction of viral toxins
Ø Exposure to elevated temperature
Ø Exposure to other toxic substances
The detailed signaling mechanism of TNF-mediated extrinsic pathway of apoptosis is summarized below:
Ø TNF first binds to its receptor called TNFR1 (Tumor Necrosis Factor Receptor-1) present on the plasma membrane.
Ø TNFR1 is a member of death receptor family proteins that turn on the apoptotic cell death process in eukaryotic cells.
Ø TNFR1 is a trans-membrane receptor with an external ligand binding domain and a cytosolic domain.
Ø The TNRF1 in the plasma membrane is presented as a pre-assembled trimer.
Ø The cytosolic domain of each TNFR1 subunit contains a segment of about 70 amino acids called ‘death domain’.
Ø Binding of TNF to the TNFR1 receptor cause a conformational change in the death domain.
Ø This conformational change in the ‘death domain’ cause the recruitment of many apoptosis-related adaptor protein factors.
Ø To the activated death domain, two cytosolic adaptor proteins (TRADD and FADD) and Pro-caspase-8 residues are binds to form a multi-protein complex.
Ø The cytosolic death domain of TNFR1, TRADD and FADD interact with one another by homologous regions present on each protein.
Ø Pro-caspase-8 and FADD possess a homologous region called ‘death effector domain’.
Ø The death effector domains of both pro-caspase-8 and FADD interacts each other.
Ø Due to these interactions, the two Pro-caspase-8 molecules cleave each other to generate an active caspase-8.
Ø A single active caspase-8 contains four polypeptide segments derived from two pro-caspases.
Ø Activated caspase-8 is an initiator caspase in the extrinsic pathway of apoptosis, they activate the downstream caspases
Ø Downstream caspases are called executioner caspases (caspase-3) that carry out the self-destruction process (apoptosis) of the cell.
Another commonly observed extrinsic pathway of apoptosis in human is by the killer lymphocytes through Fas ligand and Fas protein by the mechanism given below:
Ø Killer lymphocytes can induce apoptosis by producing a protein called Fas ligand.
Ø The Fas ligand binds to its receptor called Fas on the plasma membrane of the target cell.
Ø Similar to the death domain of TNFR1, the Fas protein can recruit intracellular adapter proteins that can aggregate Pro-caspase-8 molecules.
Ø The pro-caspase-8 molecules are then activated to caspase 8 and that in turn can activate the downstream executioner caspase (caspase-3) to induce apoptosis.
The Embryo Project Encyclopedia
The Hayflick Limit is a concept that helps to explain the mechanisms behind cellular aging. The concept states that a normal human cell can only replicate and divide forty to sixty times before it cannot divide anymore, and will break down by programmed cell death or apoptosis. The concept of the Hayflick Limit revised Alexis Carrel's earlier theory, which stated that cells can replicate themselves infinitely. Leonard Hayflick developed the concept while at the Wistar Institute in Philadelphia, Pennsylvania, in 1965. In his 1974 book Intrinsic Mutagenesis, Frank Macfarlane Burnet named the concept after Hayflick. The concept of the Hayflick Limit helped scientists study the effects of cellular aging on human populations from embryonic development to death, including the discovery of the effects of shortening repetitive sequences of DNA, called telomeres, on the ends of chromosomes. Elizabeth Blackburn, Jack Szostak and Carol Greider received the Nobel Prize in Physiology or Medicine in 2009 for their work on genetic structures related to the Hayflick Limit.
Carrel, a surgeon in the early twentieth century France working on cultures of chick heart tissue, argued that cells can infinitely replicate. Carrel claimed that he had been able to have those heart cells replicate in culture for greater than twenty years. His experiments on chick heart tissue supported the theory of infinite replication. Scientists tried to replicate Carrel's work many times, but these repeated experiments never confirmed Carrel's findings.
Hayflick worked for the Wistar Institute in 1961 where he observed that human cells do not replicate infinitely. Hayflick and Paul Moorhead described the phenomenon in a paper titled "The serial cultivation of human diploid cell strains." Hayflick's job at the Wistar Institute was to provide cell cultures to scientists who conducted experiments at the Institute, but Hayflick pursued his own research on the effects of viruses in cells. In 1965, Hayflick further detailed the concept of the Hayflick Limit in cells in a paper titled "The limited in vitro lifetime of human diploid cell strains."
In that article, Hayflick concluded that a cell could complete mitosis, or cellular duplication and division, only forty to sixty times before undergoing apoptosis and subsequent death. The conclusion held for many cell types, whether they were adult cells or fetal cells. Hayflick hypothesized that the limited replicative capability of the cell related to aging in cells and, consequently, to human aging.
The publication of Hayflick's experiments disconfirmed Carrel's theory about indefinite cellular replication. Some, such as Harry Rubin at the University of California at Berkeley in Berkeley, California, argued in the 1990s that the Hayflick Limit pertained only to damaged cells. Rubin suggested that cellular damage could result from the cells being in an environment that differed from their original environment in the body, or when researchers subjected the cells to laboratory practices.
Regardless of the criticism, other scientists used Hayflick's theory in support of further studies about cellular aging, especially with research in telomeres, which are repetitive sequences of DNA at the ends of chromosomes. Telomeres protect the chromosome from folding in on itself, and they decrease mutations in the DNA. In 1973, Alexey Olovnikov, in Russia, applied Hayflick's theories of cell death to his studies of the ends of chromosomes that did not replicate themselves during mitosis. He said that the process of cell division ends once the cell cannot replicate the ends of their chromosomes.
Although Olovnikov applied Hayflick's theory to his experiments, Olovnikov did not name Hayflick's theory. One year later in 1974, Burnet coined the term Hayflick Limit in his work, Intrinsic Mutagenesis. Burnet's work focused on the claim that age was intrinsic to the cells in each species and that they followed the Hayflick Limit, thus establishing a programmed age in which an organism would die. Elizabeth H. Blackburn at the University of California San Francisco in San Francisco, California, and Jack W. Szostak at Harvard Medical School in Boston, Massachusetts, also applied Hayflick's theory of cellular aging to their research on the structures of telomeres in 1982, when they cloned and isolated telomeres. In 1989, Greider, and Blackburn further developed the theory of cellular aging to discover the enzyme that replicates telomeres, called telomerase. Greider and Blackburn found that the presence of telomerase helps cells escape programmed cell death.
With theories about the biological mechanisms behind aging, scientists expected that they could create a cure for aging. Hayflick helped found the National Institute on Aging in Bethesda, Maryland, in 1974, a branch of the National Institutes of Health in the United States. In 1982, Hayflick also became the president of the Gerontological Society of America, founded in 1945 in New York, New York. Hayflick role helped to spread the theory of the Hayflick Limit and to further counter the theory of cellular immortality as established by Carrel.
In 2009, Blackburn and Szostak received the Nobel Prize in Physiology or Medicine for their work on telomerase, in which the Hayflick Limit played an essential role.
What is Apoptosis
Apoptosis is a programmed cell death (PCD), which is a regular and controlled mechanism of the growth and development of an organism. It is also called as cellular suicide in this process, the cell itself takes part in its death. Apoptosis allows the maintaining of the balance of cell multiplication. That means, each and every cell in the body have a self-life. The common example is red blood cells, which lives only for 120 days and destroys themselves inside the body by apoptosis.
Apoptosis occurs through well-defined, consequent morphological changes. The cell shrinks by drying, condenses and finally gets fragmented. Condensation of chromatin in the nucleus is a hallmark of apoptosis. Small membrane-bound vesicles called apoptotic bodies are formed, containing the cell contents. Hence during apoptosis, no release of the content of the cell into the extracellular environment is observed, without generating an inflammatory response. In contrast, cell death responding to the tissue damage in necrosis exhibit distinct morphological changes to apoptosis.
Figure 1: Structural changes during apoptosis compared to the necrosis
Saul Rosenberg, Ph.D.
Abbott Park, IL
Dr. Saul H. Rosenberg received his B.S. degree from the Massachusetts Institute of Technology in Boston in 1979 and then moved to the University of California at Berkeley where he earned a Ph.D. degree in organic chemistry in the laboratories of Professor Henry Rapoport. In 1984, he joined Abbott Laboratories beginning his career in the area of cardiovascular research where he discovered the renin inhibitor zankiren. He subsequently moved into the cancer research field and currently holds the title of Senior Director at Abbott. In this capacity, he has overseen the advancement of 10 compounds to the status of clinical candidate, including Bcl-2 family inhibitor ABT-263 and PARP inhibitor veliparib. He has authored more than 120 publications, is an inventor on 25 U.S. patents, and has been invited speak at numerous venues. His current research efforts are focused on the areas of apoptosis and cell cycle regulation.
John Abrams, Ph.D.
University of Texas Southwestern Medical Center
Dr. Abrams completed his Ph.D. at Stanford University in California after completing his undergraduate degree at Cornell University in Ithaca, New York. He joined the University of Texas Southwestern Medical Center in 1994 as an assistant professor in the Department of Cell Biology, becoming an associate professor in 2000 and program chair of the genetics and development graduate program in 2004. Dr. Abrams has been professor of cell biology since 2006 his research examines the in vivo molecular networks involved in cell death regulation and explores determinants of chromatin organization, using Drosophila as a model system. Dr. Abrams is an Ellison Foundation Scholar and a member on the Faculty of 1000. His publication record includes invited book chapters and many top international peer-reviewed journals he also holds three patents.
Joseph T. Opferman, Ph.D.
St. Jude Children's Research Hospital
Dr. Joseph Opferman obtained his B.S. at the University of Notre Dame and his Ph.D. in immunology at the University of Chicago. He stayed on in Chicago to do his postgraduate training in cellular immunology and development before moving to Harvard Medical School to become a postdoctoral fellow in the lab of Stanley Korsmeyer. Dr. Opferman is currently an adjunct Assistant Professor in Molecular Sciences at the University of Tennessee Health Science Center and assistant professor at St. Jude Children’s Research Hospital in the Department of Biochemistry. His research interests include investigating the development and regulation of the immune system, including apoptotic and hematopoietic pathways, and growth factor signaling in the regulation of homeostasis.
Sean Sanders, Ph.D.
Dr. Sanders did his undergraduate training at the University of Cape Town, South Africa, and his Ph.D. at the University of Cambridge, UK, supported by the Wellcome Trust. Following postdoctoral training at the National Institutes of Health and Georgetown University, Dr. Sanders joined TranXenoGen, a startup biotechnology company in Massachusetts working on avian transgenics. Pursuing his parallel passion for writing and editing, Dr. Sanders joined BioTechniques as an editor, before joining Science/AAAS in 2006. Currently, Dr. Sanders is the Director and Senior Editor for Custom Publishing for the journal Science and Program Director for Outreach.
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