Downregulation of mitochondrial telomerase reverse transcriptase induced by H2O2 is Src kinase dependent

Büchner, Nicole; Zschauer, Tim-Christian; Lukosz, Margarete; Altschmied, Joachim; Haendeler, Judith

doi:10.1016/j.exger.2010.03.003

Cited by 44 publications

(48 citation statements)

References 25 publications

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“…Intriguingly, the same group demonstrated that TERT is also degraded by oxidative stress within the mitochondria in primary human endothelial cells. Interestingly, this depletion was also dependent on Src phosphorylation of tyrosine 707 in the TERT protein [146]. The authors detected that both Src kinase and AKT1 localised to mitochondria.…”

Section: Tert In Mitochondriamentioning

confidence: 94%

“…AKT1 has also been shown to shuttle between the nucleus and the mitochondria, depending on the redox status of the cell [149]. The findings of Buechner et al suggest that there might be similar regulatory signalling mechanisms in the nucleus and other compartments such as mitochondria [146]. Intriguingly, the same Src kinase phosphorylation that activates nuclear exclusion of telomerase under increased oxidative stress seems to be responsible for the degradation of the protein within mitochondria.…”

Section: Tert In Mitochondriamentioning

confidence: 96%

“…An increasing number of proteins previously discovered in other subcellular localisations are now recognised to localise within this organelle [147]. The authors revealed that Src kinase was activated upon H 2 O 2 treatment, while AKT1 activity was reduced under these conditions [146]. Src kinase had previously been shown to interfere with mitochondrial respiration [148], while AKT is known to activate telomerase catalytic activity post-translationally [76,133] and also to modify the nuclear localisation signal of TERT responsible for its nuclear import [132].…”

Section: Tert In Mitochondriamentioning

confidence: 97%

“…Schematic drawing of shuttling of hTERT from nucleus to mitochondria. In both organelles Src kinase phosphorylates tyrosine 707 [108,146], which then results in hTERT nuclear exclusion or degradation within mitochondria. The mitochondrial localisation signal (MLS) is responsible for the direction of TERT to the mitochondria [107] while the nuclear exclusion signal is involved in transport of TERT out of the nucleus [128].…”

Section: Tert In Mitochondriamentioning

confidence: 99%

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Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress

Saretzki

2014

CPD

135

104

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Telomerase activity is essential for human cancer cells in order to maintain telomeres and provide unlimited proliferation potential and cellular immortality. However, additional non-telomeric roles emerge for the telomerase protein TERT that can impact tumourigenesis and cancer cell properties. This review summarises our current knowledge of non-telomeric functions of telomerase in human cells, with a special emphasis on cancer cells. Non-canonical functions of telomerase can be performed within the nucleus as well as in other cellular compartments. These telomereindependent activities of TERT influence various essential cellular processes, such as gene expression, signalling pathways, mitochondrial function as well as cell survival and stress resistance. Emerging data show the interaction of telomerase with intracellular signalling pathways such as NF-κB and WNT/β-catenin; thereby contributing to inflammation, epithelial to mesenchymal transition (EMT) and cancer invasiveness. All these different functions might contribute to tumourigenesis, and have serious consequences for cancer therapies due to increased resistance against damaging agents and prevention of cell death. In addition, TERT has been detected in non-nuclear locations such as the cytoplasm and mitochondria. Within mitochondria TERT has been shown to decrease ROS generation, improve respiration, bind to mitochondrial DNA, increase mitochondrial membrane potential and interact with mitochondrial tRNAs. All these different non-telomere-related mechanisms might contribute towards the higher resistance of cancer cells against DNA damaging treatments and promote cellular survival. Understanding these different mechanisms and their complexity in cancer cells might help to design more effective cancer therapies in the future.

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Section: Tert In Mitochondriamentioning

confidence: 94%

Section: Tert In Mitochondriamentioning

confidence: 96%

Section: Tert In Mitochondriamentioning

confidence: 97%

Section: Tert In Mitochondriamentioning

confidence: 99%

See 2 more Smart Citations

Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress

Saretzki

2014

CPD

135

104

View full text Add to dashboard Cite

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“…Human TERT overexpression studies have shown that full-length hTERT augments mitochondrial function and maintains the integrity of mitochondria DNA under oxidative stress in a context dependent manner. [156][157][158] Remarkably, overexpression of dominant-negative mutant TERT abrogated or reversed some of these mitochondrial changes, pointing to a potential counter-regulatory role of hTERT alternative splice variants against full-length hTERT in regulating mitochondrial function. 158 This putative interplay between hTERT isoforms hold much significance in settings such as embryonic stem cells where mitochondria (and metabolism) likely play critical roles in governing the stress response, cell fate decisions, and pluripotency.…”

Section: 135mentioning

confidence: 99%

The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance

2016

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Telomeres are linear guanine-rich DNA structures at the ends of chromosomes. The length of telomeric DNA is actively regulated by a number of mechanisms in highly proliferative cells such as germ cells, cancer cells, and pluripotent stem cells. Telomeric DNA is synthesized by way of the ribonucleoprotein called telomerase containing a reverse transcriptase (TERT) subunit and RNA component (TERC). TERT is highly conserved across species and ubiquitously present in their respective pluripotent cells. Recent studies have uncovered intricate associations between telomeres and the self-renewal and differentiation properties of pluripotent stem cells. Interestingly, the past decade's work indicates that the TERT subunit also has the capacity to modulate mitochondrial function, to remodel chromatin structure, and to participate in key signaling pathways such as the Wnt/b-catenin pathway. Many of these non-canonical functions do not require TERT's catalytic activity, which hints at possible functions for the extensive number of alternatively spliced TERT isoforms that are highly expressed in pluripotent stem cells. In this review, some of the established and potential routes of pluripotency induction and maintenance are highlighted from the perspectives of telomere maintenance, known TERT isoform functions and their complex regulation.

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Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell‐based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies

Babizhayev

Yegorov

2015

J Biomedical Materials Res

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Accumulated data indicate that wound-care products should have a composition equivalent to that of the skin: a combination of particular growth factors and extracellular matrix (ECM) proteins endogenous to the skin, together with viable epithelial cells, fibroblasts, and mesenchymal stem cells (MSCs). Strategies consisting of bioengineered dressings and cell-based products have emerged for widespread clinical use; however, their performance is not optimal because chronic wounds persist as a serious unmet medical need. Telomerase, the ribonucleoprotein complex that adds telomeric repeats to the ends of chromosomes, is responsible for telomere maintenance, and its expression is associated with cell immortalization and, in certain cases, cancerogenesis. Telomerase contains a catalytic subunit, the telomerase reverse transcriptase (hTERT). Introduction of TERT into human cells extends both their lifespan and their telomeres to lengths typical of young cells. The regulation of TERT involves transcriptional and posttranscriptional molecular biology mechanisms. The manipulation, regulation of telomerase is multifactorial in mammalian cells, involving overall telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Reactive oxygen species (ROS) have been implicated in aging, apoptosis, and necrosis of cells in numerous diseases. Upon production of high levels of ROS from exogenous or endogenous generators, the redox balance is perturbed and cells are shifted into a state of oxidative stress, which subsequently leads to modifications of intracellular proteins and membrane lipid peroxidation and to direct DNA damage. When the oxidative stress is severe, survival of the cell is dependent on the repair or replacement of damaged molecules, which can result in induction of apoptosis in the injured with ROS cells. ROS-mediated oxidative stress induces the depletion of hTERT from the nucleus via export through the nuclear pores. Nuclear export is initiated by ROS-induced phosphorylation of tyrosine 707 within hTERT by the Src kinase family. It might be presumed that protection of mitochondria against oxidative stress is an important telomere length-independent function for telomerase in cell survival. Biotechnology companies are focused on development of therapeutic telomerase vaccines, telomerase inhibitors, and telomerase promoter-driven cell killing in oncology, have a telomerase antagonist in late preclinical studies. Anti-aging medicine-oriented groups have intervened on the market with products working on telomerase activation for a broad range of degenerative diseases in which replicative senescence or telomere dysfunction may play an important role. Since oxidative damage has been shown to shorten telomeres in tissue culture models, the adequate topical, transdermal, or systemic administration of antioxidants (such as, patented ocular administration of 1% N-acetylcarnosine lubricant eye drops in the treatment of cataracts) may be beneficial at preserving telomere lengths a...

show abstract

Downregulation of mitochondrial telomerase reverse transcriptase induced by H2O2 is Src kinase dependent

Cited by 44 publications

References 25 publications

Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress

Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress

The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance

Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell‐based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies

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