Telomeres Telomerase And Cancer Pdf

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Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique.

Telomeres and Telomerase in Cancer

Journal of Cancer. International Journal of Biological Sciences. International Journal of Medical Sciences. Journal of Genomics. Global reach, higher impact. Stephanie Wang 1 , Chikezie O.

Telomeres are highly conservative repeated nucleotide sequences at the ends of linear chromosomes. Allowing effective DNA replication to keep the integrity of gene structure and the stability of chromosomes, telomeres protect the ends of the chromosome from deterioration or from fusion with neighboring chromosomes.

Reduction in the telomere length leads to the cessation of cell division and thus cellular senescence. On the other hand, telomerase is a ribonucleoprotein complex with reverse transcriptase activity, protecting the telomere from being shortened.

Thus, it is inactivated by synthesis and adds the repeated sequences onto the telomeres. Telomerase plays an important role in cell senescence and tumor formation. Telomere length and telomerase activity may be mediated by immune, endocrine, and metabolic pathways and accelerate cellular dysfunction, ageing, and even induce cancer over one's lifespan.

Significant attainment of telomerase to maintain telomere length could stop the cell senescence and aging related disease and also is required for the evolution of malignancy. This review discusses the role of telomeres and telomerase in humans during senescence and cancer. The evidence indicates that telomerase-induced telomere length manipulations could be targeted for anti-aging and anti-cancer therapy in the future.

The relationship between aging and cancer is one of the most important subjects in human studies. Both are caused by cellular damage and regulated by the cellular damage stress regulation gene. Aging is an inevitable time-dependent degenerative disease in human beings that causes irreversible accumulation of disadvantageous mutations, cell division inability, increasing disease sensitivity, and eventually death.

His study proved that telomere shortening in humans eventually makes cell division impossible. This is the first-time people correlated telomere shortening with cell aging. On the other side, the deficiencies in telomerase shorten telomeres and curtail the lifespan of mice. Since research has been found supporting that potentially harmful environmental factors or diseases are associated with short telomeres in humans, comparatively short telomere length has become the standard of poor health regardless of the person's age.

In contrast, dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptotic pathways, but they can also promote tumor initiation. Telomerase protects telomeres from being shortened by adding repeated sequences. This overexpression of telomerase confers limitless replicative potential to tumor cells by abnormal continuous elongation of telomeres. Kim found that telomerase is activated in human malignant tissues but not in adjacent normal tissues.

Recently, valuable research from various laboratories has provided major insights into telomerase and telomeres, leading to their use as diagnostic and prognostic indicators in several types of cancer.

This review is an attempt to systematically analyze the role of telomeres and telomerase in regulating cell aging and cancer and the prospects for their use in anti-aging and anti-cancer.

In humans, telomeres are composed of highly conservative repetitive nucleotide sequences and associated proteins. This triple-stranded structure is called a displacement loop or D-loop. In human, shelterin is a significant protein complex that comprises six subunits and forms a cap structure, T-loop, at the end of chromosomes. Shelterin plays an important role in protecting chromosomal ends from all aspects of the DNA damage response and regulating telomere maintenance by telomerase.

Telomeres are special nucleoprotein structures that cap the termini of chromosomes. The end of the telomere inserts back into the main body of the telomere to form the T-loop red and D-loop blue. Telomeric DNA is coated by shelterin proteins that regulate chromosomal end protection. As the biological clock of cells, progressive telomere shortening has an extremely important effect on cellular senescence and cancer.

In the absence of a DNA template, telomerase extends telomeric oligonucleotide ends with its own RNA template and compensates for the missing telomere ends during cell division. The telomerase ribonucleoprotein complex actively maintains telomere length and resists telomere shortening. However, there is almost undetectable telomerase activity in normal human somatic cells.

Therefore, human physiological aging is accompanied by the lowering telomerase activity and shortening of telomeres. This is also thought to be the basis of aging and age-related diseases and the life span of the body. Telomere shortening is the primary molecular cause of aging and the age-related diseases.

Telomere shortening induces chromosomal instability triggering the different telomere-targeted diseases, including tumors. A summary of telomere-related diseases, molecular mechanisms of telomeres, and recent advancement in the clinical development are described in Table 1. One of the main characteristics of the immune system is the constant renewal of its cells. At the same time, this renewal is highly dependent on the efficiency of telomere maintenance.

Unlike somatic cells, lymphocytes have a robust capability to proliferate given their clonal expansion and have telomerase overexpression. The telomerase overexpression prevents significant telomere shortening during each division. Immunosenescence, referring to the immune function deregulation, makes elderly individuals prone to not only infectious diseases but also to malignancy and autoimmunity. CD28 is one of the molecules expressed in T cells that provide costimulatory signals that are required for T-cell activation, T-cell proliferation, cytokine production, and T-cell survival promotion.

In elderly individuals with chronic viral infections and autoimmune diseases e. The presence of CD28 - T cells in both elderly individuals and patients with autoimmune diseases ADs has supported the concept that ADs are closely related to the cell aging process.

Due to close relationship between telomere length and coronary heart disease, genome-wide association studies have mapped leukocyte telomere length-associated single-nucleotide polymorphisms SNPs to genetic loci.

Genetic risk scores GRSs based on these SNPs were developed to predict susceptibility to cardiovascular disease and major cancers. When the GRS predicts short leukocyte telomere length, the probability of developing cardiovascular disease is increased.

Their finding supports a causal role of telomere-length variation in some age-related diseases. Hyperlipidemia is an early and main cause of coronary heart disease. These effects were pdependent and reversed in vivo by treatment of hypercholesterolemic mice with antioxidant N-acetylcysteine.

These results proved that hypercholesterolemia is also related to short telomere length. There is a growing body of evidence in support of an association between short telomeres and type 2 diabetes. It is proved that telomerase is important in maintaining glucose homeostasis in mice. The authors found that individuals in the lowest quartile of leukocyte telomere length were at almost twice the risk of developing diabetes compared with those with longer telomeres.

Genetic defects in telomere maintenance and repair cause telomere disease, like bone marrow failure, liver cirrhosis, and pulmonary fibrosis.

In , Dr. Danielle M. Townsley found that treatment with danazol, androgens, led to telomere elongation in patients with telomere diseases. Telomere depletion is closely related to cell senescence. Diabetes, coronary heart disease, psychological stress, hormones, and high blood pressures are all risk factors to accelerate telomere shortening. As previously mentioned, telomere shortening is characteristic of normal cells, and telomerase is the main mechanism regulating telomere elongation. In humans, telomerase activity is known to be only up-regulated in the cells that need to maintain an active proliferative and renewal potential, such as embryonic stem cells and germ-line cells.

Horn and Dr. Huang investigated the correlation of mutations within the core promoter of telomerase reverse transcriptase TERT , the gene coding for the catalytic subunit of telomerase, with melanoma in mouse and human respectively.

These studies proved that somatic mutations in regulatory regions of the genome of telomerase may represent an important tumorigenic mechanism.

This result has led to the proposition that telomerase inhibition may result in the cessation of tumor growth. It is currently known that replicative senescence arises when progressive reduction of telomere length ends up with t-loop collapse and dysfunctional telomeres. Similarly, telomere dysfunction, driven by shelterin modification, can also results in end-to-end chromosome fusions.

Telomere dysfunction leads to DNA-damage signaling and activation of a series of cascade amplification reactions, which activates a series of the tumor-suppressor protein, including p P53 can prompt either cellular senescence or apoptosis and plays a critical role in protecting tissues against the tumors. The pdependent response to dysfunctional telomeres serves as a strong brake to tumor development in mouse models. Unchecked telomere shortening drives chromosomal end-to-end fusions and cycles of chromosome fusion-bridge-breakage.

The study on incipient cancer cells confirmed that these telomeres must disable p53 signaling to avoid senescence and eventually up-regulate telomerase to achieve cellular immortality. Animal studies where telomeres were rendered dysfunctional following conditional removal or hypomorphic mutations of shelterin proteins in combination with p53 mutations have indicated a high likelihood of tumor genesis.

In all, these findings demonstrate that telomere uncapping, either through loss of the G-rich overhang itself or by critically shortening the n TTAGGG tract of DNA, can trigger, in the setting of p53 deficiency, the genome instability that promotes the development of epithelial cancers. It has been found that telomerase deficiency may promote the early progression of cancer by increasing chromosomal instability.

Subsequently, telomerase activation causes tumor cells to unlimitedly proliferate. There are other mechanisms to regulate telomere length, especially in cancer cells.

Regarding the important role of telomerase in the maintenance of tumor cell growth, telomerase inhibitors have been considered as potential therapies for the treatment of tumors. Bruedigam found that telomerase inhibitors, which competitively bind telomerase RNA component TERC, can effectively inhibit the incidence of acute myeloid leukemia and recurrence after chemotherapy.

However, this approach takes the risk of causing cancer. So this treatment strategy should be performed carefully to ensure that it does not induce cancer development in patients with a deficiency in tumor suppressor mechanisms. In humans, aging is the process of the accumulation of physical and psychological changes over time.

The main mechanism leading to senescence may be progressive DNA damage and progressive shortening of telomere length. Olovnikov first proposed the "telomere theory" of aging and found cellular senescence may be caused by loss of cell renewal ability due to some telomere-related gene mutation. Harley refined this theory in , arguing that the mechanism of cellular senescence is that highly differentiated somatic telomerase is inhibited and cannot compensate the telomere DNA loss during cell replication; thus, telomere length continues to decrease.

When shortened to the critical limit, the telomeres trigger the signal that terminates cell division and activates the tumor suppressor gene, p53 or Rb gene, irreversibly preventing cell mitosis.

Most of the cells die, with very few cells escaping death by activating telomerase, meaning that a small part of the cells gets "immortalized" into an infinitely proliferating cell. This is also a popular topic in the anti-aging field. Blackbum discovered that the telomeres have two states, capped and uncapped states.

Telomere structure and telomerase in health and disease (Review)

Despite a strong correlation between telomerase activity and malignancy, the outcome of telomerase inhibition in human tumor cells has not been examined. Here, we have addressed the role of telomerase activity in the proliferation of human tumor and immortal cells by inhibiting TERT function. Inducible dominant-negative mutants of hTERT dramatically reduced the level of endogenous telomerase activity in tumor cell lines. Clones with short telomeres continued to divide, then exhibited an increase in abnormal mitoses followed by massive apoptosis leading to the loss of the entire population. This cell death was telomere-length dependent, as cells with long telomeres were viable but exhibited telomere shortening at a rate similar to that of mortal cells. It appears that telomerase inhibition in cells with short telomeres lead to chromosomal damage, which in turn trigger apoptotic cell death. These results provide the first direct evidence that telomerase is required for the maintenance of human tumor and immortal cell viability, and suggest that tumors with short telomeres may be effectively and rapidly killed following telomerase inhibition.

Journal of Cancer. International Journal of Biological Sciences. International Journal of Medical Sciences. Journal of Genomics. Global reach, higher impact.

PDF | There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer. Normal.

Telomere shortening and apoptosis in telomerase-inhibited human tumor cells

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Review Series Free access Phone: Find articles by McNally, E. Find articles by Luncsford, P. Find articles by Armanios, M.

Telomere shortening and apoptosis in telomerase-inhibited human tumor cells

Джабба поднял брови. - Хорошо, это ничего не дает. Начнем вычитание.

Telomeres and Telomerase in Cancer

Бринкерхофф нахмурился. Даже директор не ставил под сомнение чутье Мидж Милкен - у нее была странная особенность всегда оказываться правой. - Что-то затевается, - заявила Мидж.  - И я намерена узнать, что .

Он в недоумении посмотрел на двухцветного. - Ты сказал - в два ночи. Панк кивнул и расхохотался. - Похоже, ты облажался, приятель. - Но сейчас только без четверти.

hindrance of cancer cell growth by interfering with telomere maintenance. targeting the components of telomerase enzyme directly to prevent telomere.

Long telomeres and cancer risk: the price of cellular immortality

Я тоже хотел бы с ней покувыркаться. Заплачу кучу денег. Хотя спектакль и показался достаточно убедительным, но Беккер зашел слишком. Проституция в Испании запрещена, а сеньор Ролдан был человеком осторожным. Он уже не один раз обжигался, когда полицейские чиновники выдавали себя за похотливых туристов.

Он нащупал в кармане пиджака пистолет. До сих пор Дэвиду Беккеру необыкновенно везло, и не следует и дальше искушать судьбу.


  1. Nathan S. 10.05.2021 at 11:48

    Current therapies for breast cancer include treatments that are toxic and often result in drug resistance.

  2. Vaden B. 13.05.2021 at 04:54

    PDF | On Mar 1, , Carol W. Greider and others published Telomeres, Telomerase and Cancer | Find, read and cite all the research you.

  3. Treeplondipel 15.05.2021 at 06:39

    The ends of the eukaryotic chromosomes have special properties when compared with chromosomal ends created by stochastic breakdown.

  4. Kaukel M. 15.05.2021 at 15:55

    Telomeres and telomerase are the pivotal players that destine cellular senescence and immortalization.