InTERTesting association between telomerase, mTOR and phytochemicals

2012 ◽  
Vol 14 ◽  
Author(s):  
Tabetha Sundin ◽  
Patricia Hentosh
Keyword(s):  
Dna Sequences ◽  
Mammalian Target Of Rapamycin ◽  
Heat Shock Protein 90 ◽  
Protein Translation ◽  
Telomerase Activity ◽  
Gene Coding ◽  
Functional Complex ◽  
Telomerase Regulation ◽  
Rate Limiting

Telomeres are stretches of repeated DNA sequences located at the ends of chromosomes that are necessary to prevent loss of gene-coding DNA regions during replication. Telomerase – the enzyme responsible for immortalising cancer cells through the addition of telomeric repeats – is active in ~90% of human cancers. Telomerase activity is inhibited by various phytochemicals such as isoprenoids, genistein, curcumin, epigallocatechin-3-gallate, resveratrol and others. Human TERT (telomerase reverse transcriptase – the rate-limiting component of telomerase), heat shock protein 90, Akt, p70 S6 kinase (S6K) and mammalian target of rapamycin (mTOR) form a physical and functional complex with one another. The inclusion of Akt, mTOR and S6K in the TERT complex is compelling evidence to support mTOR-mediated control of telomerase activity. This review will define the role of mTOR, the master regulator of protein translation, in telomerase regulation and provide additional insights into the numerous ways in which telomerase activity is hindered by phytochemicals.

scholarly journals Role of a Functional SNP of the Gene Coding Brain Serotonin Synthesis Rate-Limiting Enzyme Tph2 in Dilated Cardiomyopathy

2020 ◽  
Vol 118 (3) ◽  
pp. 426a
Author(s):  
Sachio Morimoto ◽  
Kengo Hayamizu ◽  
Miki Nonaka ◽  
Lei Li ◽  
Yuanyuan Wang
Keyword(s):  
Dilated Cardiomyopathy ◽  
Brain Serotonin ◽  
Synthesis Rate ◽  
Serotonin Synthesis ◽  
Gene Coding ◽  
Rate Limiting ◽  
Functional Snp

The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis

2013 ◽  
Vol 41 (4) ◽  
pp. 939-943 ◽  
Author(s):  
Elaine A. Dunlop ◽  
Andrew R. Tee
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Protein Kinases ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Status ◽  
Protein Translation ◽  
Cellular Growth ◽  
Target Of Rapamycin ◽  
Amp Activated Protein Kinase ◽  
Rate Limiting

In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as lipids and amino acids. Consequently, the energy and nutrient status of the cell is acutely monitored and carefully maintained. mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] is often considered to be the master regulator of cell growth that enhances cellular biomass through up-regulation of protein translation. In order for cells to control cellular homoeostasis during growth, there is close signalling interplay between mTORC1 and two other protein kinases, AMPK (AMP-activated protein kinase) and ULK1 (Unc-51-like kinase 1). This kinase triad collectively senses the energy and nutrient status of the cell and appropriately dictates whether the cell will actively favour energy- and amino-acid-consuming anabolic processes such as cellular growth, or energy- and amino-acid-generating catabolic processes such as autophagy. The present review discusses important feedback mechanisms between these three homoeostatic protein kinases that orchestrate cell growth and autophagy, with a particular focus on the mTORC1 component raptor (regulatory associated protein of mammalian target of rapamycin), as well as the autophagy-initiating kinase ULK1.

scholarly journals Human Telomerase and Its Regulation

2002 ◽  
Vol 66 (3) ◽  
pp. 407-425 ◽  
Author(s):  
Yu-Sheng Cong ◽  
Woodring E. Wright ◽  
Jerry W. Shay
Keyword(s):  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Telomerase Activity ◽  
Cellular Aging ◽  
Telomeric Dna ◽  
Associated Proteins ◽  
Functional Complex ◽  
Length Regulation ◽  
Normal Human ◽  
Human Telomerase

SUMMARY The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

scholarly journals Coupling nutrient sensing to metabolic homoeostasis: the role of the mammalian target of rapamycin complex 1 pathway

2012 ◽  
Vol 71 (4) ◽  
pp. 502-510 ◽  
Author(s):  
Caroline André ◽  
Daniela Cota
Keyword(s):  
Energy Balance ◽  
Metabolic Diseases ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Nutrient Sensing ◽  
Target Of Rapamycin ◽  
Mitochondrial Activity ◽  
Peripheral Tissues ◽  
Mtorc1 Pathway

The mammalian target of rapamycin complex 1 (mTORC1) pathway is known to couple different environmental cues to the regulation of several energy-demanding functions within the cell, spanning from protein translation to mitochondrial activity. As a result, at the organism level, mTORC1 activity affects energy balance and general metabolic homoeostasis by modulating both the activity of neuronal populations that play key roles in the control of food intake and body weight, as well as by determining storage and use of fuel substrates in peripheral tissues. This review focuses on recent advances made in understanding the role of the mTORC1 pathway in the regulation of energy balance. More particularly, it aims at providing an overview of the status of knowledge regarding the mechanisms underlying the ability of certain amino acids, glucose and fatty acids, to affect mTORC1 activity and in turn illustrates how the mTORC1 pathway couples nutrient sensing to the hypothalamic regulation of the organisms’ energy homoeostasis and to the control of intracellular metabolic processes, such as glucose uptake, protein and lipid biosynthesis. The evidence reviewed pinpoints the mTORC1 pathway as an integrator of the actions of nutrients on metabolic health and provides insight into the relevance of this intracellular pathway as a potential target for the therapy of metabolic diseases such as obesity and type-2 diabetes.

scholarly journals Telomerase Regulation: A Role for Epigenetics

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1213
Author(s):  
Fatma Dogan ◽  
Nicholas R. Forsyth
Keyword(s):  
Cellular Transformation ◽  
Telomerase Activity ◽  
Limiting Factor ◽  
Systematic Analysis ◽  
Diagnosis And Prognosis ◽  
Development And Differentiation ◽  
Telomere Biology ◽  
Promoter Mutations ◽  
Telomerase Regulation

Telomerase was first described by Greider and Blackburn in 1984, a discovery ultimately recognized by the Nobel Prize committee in 2009. The three decades following on from its discovery have been accompanied by an increased understanding of the fundamental mechanisms of telomerase activity, and its role in telomere biology. Telomerase has a clearly defined role in telomere length maintenance and an established influence on DNA replication, differentiation, survival, development, apoptosis, tumorigenesis, and a further role in therapeutic resistance in human stem and cancer cells including those of breast and cervical origin. TERT encodes the catalytic subunit and rate-limiting factor for telomerase enzyme activity. The mechanisms of activation or silencing of TERT remain open to debate across somatic, cancer, and stem cells. Promoter mutations upstream of TERT may promote dysregulated telomerase activation in tumour cells but additional factors including epigenetic, transcriptional and posttranscriptional modifications also have a role to play. Previous systematic analysis indicated methylation and mutation of the TERT promoter in 53% and 31%, respectively, of TERT expressing cancer cell lines supporting the concept of a key role for epigenetic alteration associated with TERT dysregulation and cellular transformation. Epigenetic regulators including DNA methylation, histone modification, and non-coding RNAs are now emerging as drivers in the regulation of telomeres and telomerase activity. Epigenetic regulation may be responsible for reversible silencing of TERT in several biological processes including development and differentiation, and increased TERT expression in cancers. Understanding the epigenetic mechanisms behind telomerase regulation holds important prospects for cancer treatment, diagnosis and prognosis. This review will focus on the role of epigenetics in telomerase regulation.

scholarly journals Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3145
Author(s):  
Karolin Walter ◽  
Eva Rodriguez-Aznar ◽  
Monica S. Ventura Ferreira ◽  
Pierre-Olivier Frappart ◽  
Tabea Dittrich ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Pancreatic Cancer Cells ◽  
Sphere Formation ◽  
Telomerase Regulation ◽  
Pancreatic Cancer Stem Cells

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.

scholarly journals Transient Hsp90 suppression promotes a heritable change in protein translation

2018 ◽  
Author(s):  
Peter Tsvetkov ◽  
Zarina Brune ◽  
Timothy J. Eisen ◽  
Sven Heinrich ◽  
Greg A. Newby ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Heat Shock Protein 90 ◽  
Protein Translation ◽  
Translation Regulation ◽  
Hsp90 Inhibition ◽  
Transient Loss ◽  
Hsp90 Chaperone ◽  
Physical Interactions ◽  
Heritable Change

The heat shock protein 90 (Hsp90) chaperone functions as a protein-folding buffer and plays a unique role promoting the evolution of new heritable traits. To investigate the role of Hsp90 in modulating protein synthesis, we screened more than 1200 proteins involved in mRNA regulation for physical interactions with Hsp90 in human cells. Among the top hits was CPEB2, which strongly binds Hsp90 via its prion domain, reminiscent of the prion-like regulation of translation of Aplysia CPEB. In a yeast model of CPEB prion-dependent translation regulation, transient inhibition of Hsp90 amplified CPEB2 prion activity and resulted in persistent translation of the CPEB reporter. Remarkably, inhibition of Hsp90 was sufficient to induce a heritable change in protein translation that persisted for 30 generations, even in the absence of exogenous CPEB. Although we identified a variety of perturbations that enhanced translation of the reporter, only Hsp90 inhibition led to persistent activation. Thus, transient loss of Hsp90 function leads to the non-genetic inheritance of a novel translational state. We propose that, in addition to sculpting the conformational landscape of the proteome, Hsp90 promotes phenotypic variation by modulating protein synthesis.

scholarly journals Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies

Medicina ◽  
2019 ◽  
Vol 55 (12) ◽  
pp. 754 ◽  
Author(s):  
Antonio Gnoni ◽  
Antonella Licchetta ◽  
Riccardo Memeo ◽  
Antonella Argentiero ◽  
Antonio G. Solimando ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Sequences ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Therapies ◽  
Cancer Proliferation ◽  
Advanced Hcc ◽  
Alternative Pathways ◽  
Extracellular Signal

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC.

DNA methylation in satellite repeats disorders

2019 ◽  
Vol 63 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Claire Francastel ◽  
Frédérique Magdinier
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Repetitive Dna ◽  
Dna Sequences ◽  
Satellite Repeats ◽  
Tremendous Progress ◽  
Genes Encoding ◽  
Dna Elements ◽  
Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

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