In what ways can mechanisms of apoptosis be damaged?

In what ways can mechanisms of apoptosis be damaged?

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How many ways can an Apoptosis mechanism be made disfunctional or irreparably damaged? If a cell has damaged Apoptosis mechanisms and it divides will its daughter cells have such damage?

Most of us have had the apoptotic process in our B-lymphocytes disrupted when we had infectious mononucleosis, caused by the EBV virus. The EBV virus (pardon the virus-virus) encodes proteins, including one that mimics a host cell protein, Bcl-2, which plays an important role in apoptosis. The set of virus 'decoy' proteins forces the infected cell to survive and be a host to produce new virus, whereas the cell's normal response would be to apoptose. Wart viruses such as HPV may have similar mechanisms.

So in summary, excessive growth or transformation to an immortal cell typically requires activation of mechanisms that promote cell growth and the inibition of mechanisms that promote cell death. "Transforming viruses' often have mechanisms to affect both cell growth and cell death.

This answer isn't to the question 'how many ways can [the] apoptosis mechanism [… ] be damaged ', but answers 'what's a common way that apoptosis pathways can be disrupted'… large DNA transforming viruses.

Lot's of ways. Apoptosis is complex, but falls under two pathways ending up at caspase 3. Anywhere in the pathway may there be a problem but also in things that trigger the pathway. For example in cancer there is loss of tumour suppressors which ensure a damaged cell undergoes apoptosis or prevents replication and oncogenes which allow controlled replication. Damage to these genes allows a cell to divide in the absence of signals to divide and also forget to check that it's DNA isn't damaged before replicating. This is then passed on to the daughter cancer cells. As each check is removed the cell permits more and more mutations meaning more and more likelihood for the next mutation to occur. Cancer is caused literally by one cell having defects and every daughter cell also possess the defects. Those that have defects which accidentally kill the cell are selected out.

Apoptosis plays a fundamental role in many physiological processes such as tissue development, and the immune response. Thus, regulation of apoptosis is important for tissue homeostasis and its deregulation can lead to a variety of pathological conditions including carcinogenesis and chemo-resistance.

Apoptosis is mediated primarily through promoting or inhibiting the activation of caspases. Caspases are effectors of cell suicide and cleave multiple substrates, leading to biochemical and morphological changes including mitochondrial outer membrane permeabilization, cell membrane remodeling and blebbing, cell shrinkage, nuclear condensation, and DNA fragmentation.

In mammalian systems, the extrinsic death receptor pathway, the intrinsic mitochondrial pathway and endoplasmic reticulum pathway are the major signaling systems that result in the activation of the executioner/effector caspases and the consequent demise of the cell.

All pathways eventually lead to a common pathway or the execution phase of apoptosis. Understanding the apoptosis mechanisms is important and helpful to us in the understanding of the pathogenesis of conditions as a result of disordered apoptosis. Meanwhile, it may help in the development of drugs that target certain apoptotic genes or pathways.


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Reciprocal Spatiotemporally Controlled apoptosis Regulates Wolffian Duct Cloaca Fusion ⎗]

"The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT." Links: genital | testis

The interaction mechanism between autophagy and apoptosis in colon cancer

Autophagy and apoptosis play crucial roles in tumorigenesis. Recent studies have shown that autophagy and apoptosis have a cross-talk relationship in anti-tumor therapy. It is well established that apoptosis is one of the main pathways of tumor cell death. While autophagy can occurs in tumors with opposite function: protective autophagy and lethal autophagy. Protective autophagy can inhibit tumor apoptosis induced by anticancer drugs, while lethal autophagy can induce tumor cell apoptosis in cooperation with anticancer drugs. Hence, autophagy and apoptosis have synergistic and antagonistic effects in tumor. Colorectal cancer is a common malignant tumor with high morbidity and mortality. In recent years, colorectal carcinoma has achieved improved clinical efficacy with drug treatment. Nonetheless, increasing drug-resistance limit the treatment efficacy, highlighting the urgency of exploring the molecular events that drive drug resistance. Researchers have found that autophagy is one of the major factors leading to drug resistance in colon cancer. Therefore, elucidating the interaction between autophagy and apoptosis is helpful to improve the efficacy of anticancer drugs in clinical treatment of colorectal cancer. This review attaches great importance to the relationship between autophagy and apoptosis and related factors in colorectal cancer.

Cell Signaling and Cellular Metabolism

The rush of adrenaline that leads to greater glucose availability is an example of an increase in metabolism.

Learning Objectives

Explain how cellular metabolism can be altered

Key Takeaways

Key Points

  • The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic AMP.
  • Cyclic AMP activates PKA (protein kinase A), which phosphorylates two enzymes.
  • Phophorylation of the first enzyme promotes the degradation of glycogen by activating intermediate GPK that in turn activates GP, which catabolizes glycogen into glucose.
  • Phosphorylation of the second enzyme, glycogen synthase (GS), inhibits its ability to form glycogen from glucose.
  • The inhibition of glucose to form glycogen prevents a futile cycle of glycogen degradation and synthesis, so glucose is then available for use by the muscle cell.

Key Terms

  • cyclic adenosine monophosphate: cAMP, a second messenger derived from ATP that is involved in the activation of protein kinases and regulates the effects of adrenaline
  • epinephrine: (adrenaline) an amino acid-derived hormone secreted by the adrenal gland in response to stress
  • protein kinase A: a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP)

Increase in Cellular Metabolism

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells. Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway. For example, an enzyme may show large changes in activity (i.e. it is highly regulated), but if these changes have little effect on the rate of a metabolic pathway, then this enzyme is not involved in the control of the pathway.

The result of one such signaling pathway affects muscle cells and is a good example of an increase in cellular metabolism. The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic adenosine monophosphate (also known as cyclic AMP or cAMP) inside the cell. Also known as epinephrine, adrenaline is a hormone (produced by the adrenal gland attached to the kidney) that prepares the body for short-term emergencies. Cyclic AMP activates PKA (protein kinase A), which in turn phosphorylates two enzymes. The first enzyme promotes the degradation of glycogen by activating intermediate glycogen phosphorylase kinase (GPK) that in turn activates glycogen phosphorylase (GP), which catabolizes glycogen into glucose. (Recall that your body converts excess glucose to glycogen for short-term storage. When energy is needed, glycogen is quickly reconverted to glucose. ) Phosphorylation of the second enzyme, glycogen synthase (GS), inhibits its ability to form glycogen from glucose. In this manner, a muscle cell obtains a ready pool of glucose by activating its formation via glycogen degradation and by inhibiting the use of glucose to form glycogen, thus preventing a futile cycle of glycogen degradation and synthesis. The glucose is then available for use by the muscle cell in response to a sudden surge of adrenaline—the “fight or flight” reflex.

Formation of Cyclic AMP: This diagram shows the mechanism for the formation of cyclic AMP (cAMP). cAMP serves as a second messenger to activate or inactivate proteins within the cell.

In what ways can mechanisms of apoptosis be damaged? - Biology

Article Summary:

Apoptosis is the programmed cell death in which cells before dying undergo series of events. Through this way, the unnecessary cells are removed from the body or the cells which cause harm to the body. Apoptosis usually occurs during the embryonic stages when the cells are growing and developing. It can also occur in adult cells which are affected through some injury or when the tissues need to be remodeled. Aging is another factor which causes apoptosis. Process of apoptosis is also celled as cell suicide because cells use cellular machinery to kill themselves. It takes place only in multicellular organisms. It is a normal thing when the cell functions and if there is an incomplete process of apoptosis it may lead to the development of malignant and benign tumors.

What Triggers the Process of Apoptosis:-
For every process which occurs in the body, there is some reason behind it. There are numerous causes which make the process of apoptosis to take place. The most important cause is the DNA damage. When the body of the person is exposed to ionizing radiations like x-rays, ultraviolet radiations or chemotherapy medications for the treatment of cancer then apoptosis can occur. Another factor which triggers apoptosis is the corticosteroids. On the surface of the every cell there is a special type of protein called as Fas protein, it also causes the cell suicide.

How Apoptosis Takes Place:-

There are several steps involved in the programmed cell death

1) When the unnecessary enzymes start activating in the cell, they eat up the proteins due to which cell starts becoming round.

2) DNA present inside the nucleus starts separating and eventually it shrinks down.

3) There is a nuclear membrane around the nucleus, when the apoptosis starts, it degrades and cell's nucleus becomes without the outer layer.

4) Due to the absence of the nuclear membrane, the DNA molecule starts rupturing into small fragments. These fragments are not in a particular size.

5) As nucleus is no longer protected that is why it breaks down into many pieces along with the uneven pieces of DNA molecule.

6) Due to the breakage inside the cell, cell itself starts degrading through the process of blebbing.

7) Blebbing converts the cell into mall pieces which are eaten by other small cells known as phagocytes.

There are three types of apoptosis

Internal Apoptosis:-
Apoptosis can occur through internal signals. Internal signals mean when there is damage to the cell internally. Internal damage triggers a protein called BAX. This protein pricks the mitochondrial membrane. Mitochondria are the power house of the cell and they provide energy to the cell to perform various functions. Due to the puncturing of mitochondrial wall, cytochrome c releases from it and binds to the Apaf-1. This binding makes the production of apoptosomes which trigger apoptosis. These apoptosomes cause the formation of capsases. Capsases breakdown the structure of the cell and DNA destroys ultimately.

External Apoptosis:-
External signals also cause the apoptosis to occur. The Fas proteins on the surface of the cell bind to another protein called TNF or tumor necrosis factor which will in turn trigger the signal in cytoplasm and will activate capsase 8. This enzyme will lead to the formation of more capsases which will eventually breakdown the cell and destroy the DNA.

Apoptosis Inducing Factor:-
Apoptosis inducing factor also causes the cell suicide. This type of apoptosis usually occurs in the neurons which are the responsible for conducting the nerve impulses. Other cells can also undergo AIF. It is a protein present inside the mitochondrial intermembrane space. When the apoptosis starts, cell receives a signal of death and in response to this AIF is released in the cytoplasm. This protein reaches to the nucleus and destroys the DNA molecule. When DNA will be killed then there will be no activity taking place inside the cell and cell will die automatically.

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Apoptosis, necrosis, autophagy and senescence

In this section, the cell death and senescence processes will be described. Understanding of these processes contributes to insight on normal biological aging and diseases of aging.

Background: Cell damage and mitochondria 3,4,5

As noted above, normal aging is associated with increased accumulation of cellular damage. Many types of stress can cause cellular damage, including low oxygen levels, DNA alterations, low nutrient levels, and oxidative stress [exposure to increased levels of reactive oxygen species, (ROS)]. Damage from these stressors can include DNA mutations, protein unfolding, and oxidation of lipids in membranes, all of which can impair cellular function. Because mitochondria are sites of high ROS production, they are key organelles in the aging process. Mitochondria also are important organelles in the induction of apoptosis, autophagy and senescence.

Apoptosis is the process of programmed cell death. In this process, damaged cells self-destruct, and are removed by phagocytosis without triggering inflammation. Apoptosis can occur via a number of intracellular signaling pathways ROS-modified molecules can serve as triggers and/or apoptotic signaling molecules. The apoptosis pathways are strongly regulated, with intricate interplay between anti-apoptotic and pro-apoptotic factors.

Apoptosis is a vital process in normal embryogenesis and in maturation of the immune system It also facilitates organism survival by removing damaged cells without inflammatory injury to remaining cells. Research has found that apoptosis is often decreased human aging. Much remains to be learned about the actual contribution of apoptosis to normal aging.

Necrosis is the process of cell death due to injury from trauma, infection, extreme thermal stress, or other factors.In contrast to apoptosis, necrosis activates inflammation pathways that can be harmful to surrounding cells.

Autophagy is the process by which damaged molecules, organelles or cells are degraded enzymatically. The damaged entity is surrounded by a membrane and transported to the lysosome for digestion. Amino acids and other products of the digestion are then used for cell maintenance. Autophagy may or may not result in cell death. For example, if specific damaged proteins or mitochondria are autophagically removed, the process may actually assist in cell survival rather than in cell death.

Like apoptosis, autophagy is important in normal growth and development. Autophagy also decreases with normal aging which can result in accumulation of malfunctioning proteins, mitochondria and other organelles.

Senescence is the process by which damaged cells lose their ability to divide, but without cell death or neoplastic transformation. Similar to apoptosis, senescence is an important process in embryogenesis it is also in wound healing. However, senescent cells can contribute to an unhealthy environment around them by expressing inflammatory cytokines [senescence associated secretory phenotype [SASP]. DNA damage is a common initiator of the senescence pathway. Cultured senescent cells are also typically apoptosis-resistant, but it is not known if this characteristic is manifested by cells in vivo.

Molecular markers of senescent cells have been found to be increased in many aging tissues of animal models and humans. This increase is thought to indicate increased numbers of senescent cells in aging, but confirming evidence is needed. The increase in numbers of senescent cells has been linked to the pro-inflammatory phenotype often seen with aging. Increased serum inflammatory cytokines have also been documented in human aging. The higher numbers of senescent cells may also contribute to etiologies of inflammation-related diseases of aging, such as atherosclerosis. Correlation has not yet been made between numbers of senescent cells and body-wide changes of normal aging.

Which pathway is used? 4,5,6

The relationship between apoptosis, necrosis, autophagy and senescence is variable. The process is used by a cell depends on the specific tissues and cells involved, and may also be influenced by the severity of the inciting cellular stress. Milder stress may foster autophagy or senescence, with moderate stress resulting in apoptosis, and severe stress leading to necrosis.

Tissue effects in aging

This section discusses research findings regarding the relationships between tissue changes of normal aging and the processes of apoptosis, necrosis, autophagy, and senescence. Much of the current knowledge on this topic is derived from animal models. Extensive research remains yet to be done in human cells and tissues. The reader is referred to the Biology of Aging section of PM&R Knowledge NOW for more information on general organ-related changes of normal aging.

The total number of cardiac myocytes decreases by as much as 30% with age apoptosis is the primary pathway in this decrease. The heart is not able to regenerate or replace all these lost cells, so the remaining cells tend to hypertrophy. Specific inciting factors for this apoptosis are not known, although accumulated mitochondrial gene mutations appear to contribute.

Autophagy is also important for removal of damaged mitochondria in the cardiac myocytes. Exercise has been found to increase autophagy in the myocardium, and therefore may be a mechanism by which exercise is cardioprotective.

Estrogen is anti-apoptotic for osteoblasts, and pro-apoptotic for osteoclasts. Thus age-related estrogen decline may contribute to bone loss via a shift in the balance between programmed cell death and survival of these two cell types. Although increased senescence markers have been documented in bone of older persons, not enough is known yet to make any firm conclusions about the contribution of senescence to age-related bone loss in humans.

Damaged proteins and DNA have been identified in aging human discs, as have apoptotic and senescent cells. Elevated levels of senescence markers have also been identified in aged human disc, thought to indicate increased numbers of senescent cells in older discs vs. younger ones. Further study is needed to better define specifically how apoptosis and senescence relate to functional changes in aging disc tissue.

Skeletal Muscle 16,17,18,19,20

Sarcopenia is the age-related decrease of muscle mass and muscle function, characterized by muscle atrophy and decreased myofiber number. A full understanding has yet to be reached regarding the etiologic complexities of this condition. However, it has been reported that there is a decrease in skeletal muscle autophagy with aging, particularly in autophagy for damaged mitochondria (mitophagy). There is also an increase is apoptosis. This alteration in balance between muscle repair and cell death promotes accumulation of damaged mitochondria and associated increased release of ROS, as well as decreased clearance of ROS-mediated cellular injury. There is very little experimental data to date regarding cellular senescence in aging skeletal muscle.

In muscles of aged experimental animals, aerobic exercise has been found to decrease components of apoptotic pathways, and increase components of autophagy pathways as well as to mitigate muscle atrophy. Chronic training also has been found to decrease ROS production in skeletal muscle, a decrease in oxidative stress. This oxidative stress reduction may decrease muscle apoptosis however, more study is needed here.

Nervous system 17,19,21,22,23

Structural mitochondrial abnormalities have been documented in pre-synaptic axons of aged mice. DNA damage and ROS-mediated mitochondrial dysfunction have also been documented in aging alpha motor neurons such stressors can lead to apoptotic demise of these neurons. This motor nerve loss contributes to the muscle atrophy and decreased muscle cell number of sarcopenia Additionally, mitophagy is decreased in aging motor neurons, which may also contribute to alpha motor neuron loss due to accumulation of damaged organelles and proteins. Data is quite limited regarding the presence or functional significance of senescent cells in aging CNS.

In aging, there is an increase in lymphocyte apoptosis,which is thought to contribute to a decreased number of T lymphocytes.Accumulation of senescent lymphocytes may contribute to a pro-inflammatory state in aging.

Mechanisms of natural killer cell-mediated cellular cytotoxicity

Cellular cytotoxicity, the ability to kill other cells, is an important effector mechanism of the immune system to combat viral infections and cancer. Cytotoxic T cells and natural killer (NK) cells are the major mediators of this activity. Here, we summarize the cytotoxic mechanisms of NK cells. NK cells can kill virally infected of transformed cells via the directed release of lytic granules or by inducing death receptor-mediated apoptosis via the expression of Fas ligand or TRAIL. The biogenesis of perforin and granzymes, the major components of lytic granules, is a highly regulated process to prevent damage during the synthesis of these cytotoxic molecules. Additionally, NK cells have developed several strategies to protect themselves from the cytotoxic activity of granular content upon degranulation. While granule-mediated apoptosis is a fast process, death receptor-mediated cytotoxicity requires more time. Current data suggest that these 2 cytotoxic mechanisms are regulated during the serial killing activity of NK cells. As many modern approaches of cancer immunotherapy rely on cellular cytotoxicity for their effectiveness, unraveling these pathways will be important to further progress these therapeutic strategies.

Keywords: apoptosis death receptors degranulation granzyme perforin.

Watch the video: From DNA to protein - 3D (August 2022).