Modulation of telomere protection by the PI3K/AKT pathway

Méndez-Pertuz, Marinela; Martínez, Paula; Blanco‐Aparicio, Carmen; Gómez‐Casero, Elena; García, Ana; Martı́nez-Torrecuadrada, Jorge L.; Palafox, Marta; Cortés, Javier; Serra, Violeta; Pastor, Joaquı́n; Blasco, Marı́a A.

doi:10.1038/s41467-017-01329-2

Cited by 55 publications

(53 citation statements)

References 81 publications

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“…Similarly, TRF1 is known to interact with Akt, a ubiquitous serine threonine protein kinase involved in metabolism and growth factor signaling. Indeed, PI3Kα, a downstream target of Akt, has been recently identified to regulate TRF1 protein expression . Further studies elucidating these potential shelterin regulators may allow for small molecule compounds which may help improve shelterin function, reduce senescence in old arteries or CVDs thereby improving function.…”

Section: Prospective: Targeting Shelterin As a Novel Anti‐aging Strategymentioning

confidence: 99%

The role of senescence, telomere dysfunction and shelterin in vascular aging

2018

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In the United States and other westernized nations, CVDs are the leading cause of death in adults over 65 years of age. Large artery stiffness and endothelial dysfunction are increased with age and age-associated arterial dysfunction is an important antecedent of CVDs. One age-associated change that may contribute to vascular dysfunction and CVD risk is an increase in the number of resident senescent cells in the vasculature. Senescent cells display a pro-oxidant, pro-inflammatory phenotype known as the SASP. However, the mechanisms that drive the SASP and the vascular aging phenotype remain elusive. A putative mechanism is the involvement of oxidative stress and inflammation in telomere function. Telomeres are the end caps of chromosomes which are maintained by a six-protein complex known as shelterin. Disruption of shelterin can uncap telomeres and induce cellular senescence. Accordingly, in this review, we propose that oxidative stress and inflammation disrupt shelterin in vascular cells, driving telomere dysfunction and that this mechanism may be responsible for the induction of SASP. The proposed mechanisms may represent some of the initial changes that lead to vascular dysfunction in advanced age.

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Section: Prospective: Targeting Shelterin As a Novel Anti‐aging Strategymentioning

confidence: 99%

The role of senescence, telomere dysfunction and shelterin in vascular aging

2018

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“…Next, we set to study the mechanisms by which the newly identified compounds regulate TRF1 levels. We had previously reported that the TRF1 telomeric protein is regulated by the PI3K signaling pathway (Mendez‐Pertuz et al , ). In particular, TRF1 is directly phosphorylated by the PI3K downstream target AKT at different residues (T248, T330, and S344), and this phosphorylation is necessary for TRF1 stability and TRF1 foci formation in vivo (Mendez‐Pertuz et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we demonstrate that, among the AKT‐dependent phosphosites of TRF1, S344 (T358 in human) is as also a target for ERK‐mediated phosphorylation (Fig O). As negative control, we also generated a TRF1 phosphomutant in residue T248 whose phosphorylation is mediated by AKT but not ERK (Fig O; Mendez‐Pertuz et al , ). As expected, this mutant did not result in decreased TRF1 phosphorylation (Fig O).…”

Section: Resultsmentioning

confidence: 99%

“…Albeit all the mutants showed a partial rescue of the proliferation defects, mutants T330A and T335A resulted in a significantly lower proliferation rate compared with wild‐type GFP1‐TRF1 (). It is important to point out that T330 phosphosite is also essential for AKT‐mediated TRF1 phosphorylation (Mendez‐Pertuz et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…On this matter, our group performed an initial screening with the aim of identifying molecules and novel signaling pathways that modulate TRF1 binding to telomeres (Garcia‐Beccaria et al , ). We identified several compounds which belonged to the PI3K family (Mendez‐Pertuz et al , ). In particular, we found that both PI3K and AKT inhibitors significantly reduced TRF1 telomeric foci and this caused increased telomeric DNA damage and fragility (Mendez‐Pertuz et al , ).…”

Section: Discussionmentioning

confidence: 99%

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Multiple cancer pathways regulate telomere protection

et al. 2019

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Telomeres are considered as universal anti‐cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF 1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma ( GBM ) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF 1 inhibitory drugs using a collection of FDA ‐approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK , recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK 2 kinases phosphorylate TRF 1 in vitro and that these modifications are essential for TRF 1 location to telomeres in vivo . Finally, we use these new TRF 1 regulatory pathways as the basis to discover novel drug combinations based on TRF 1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient‐derived glioblastoma xenograft models.

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Comparative profiles of DNA methylation and differential gene expression in osteocytic areas from aged and young mice

et al. 2020

Cell Biochemistry & Function

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Altered DNA methylation upon ageing may result in many age‐related diseases such as osteoporosis. However, the changes in DNA methylation that occur in cortical bones, the major osteocytic areas, remain unknown. In our study, we extracted total DNA and RNA from the cortical bones of 6‐month‐old and 24‐month‐old mice and systematically analysed the differentially methylated regions (DMRs), differentially methylated promoters (DMPs) and differentially expressed genes (DEGs) between the mouse groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DMR‐related genes revealed that they were mainly associated with metabolic signalling pathways, including glycolysis, fatty acid and amino acid metabolism. Other genes with DMRs were related to signalling pathways that regulate the growth and development of cells, including the PI3K‐AKT, Ras and Rap1 signalling pathways. The gene expression profiles indicated that the DEGs were mainly involved in metabolic pathways and the PI3K‐AKT signalling pathway, and the profiles were verified through real‐time quantitative PCR (RT‐qPCR). Due to the pivotal roles of the affected genes in maintaining bone homeostasis, we suspect that these changes may be key factors in age‐related bone loss, either together or individually. Our study may provide a novel perspective for understanding the osteocyte and its relationship with osteoporosis during ageing.Significance of the studyOur study identified age‐related changes in gene expressions in osteocytic areas through whole‐genome bisulfite sequencing (WGBS) and RNA‐seq, providing new theoretical foundations for the targeted treatment of senile osteoporosis.

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Modulation of telomere protection by the PI3K/AKT pathway

Cited by 55 publications

References 81 publications

The role of senescence, telomere dysfunction and shelterin in vascular aging

The role of senescence, telomere dysfunction and shelterin in vascular aging

Multiple cancer pathways regulate telomere protection

Comparative profiles of DNA methylation and differential gene expression in osteocytic areas from aged and young mice

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