Telomerase Inhibition
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Telomerase Inhibition
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Author : Lucy Andrews
language : en
Publisher: Springer Science & Business Media
Release Date : 2007-11-29
Telomerase Inhibition written by Lucy Andrews and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007-11-29 with Medical categories.
This volume presents a compendium of the most recent and advanced methods applied to the rapidly expanding field of telomerase inhibition. The techniques described provide the researcher with a diverse and comprehensive set of tools for the study of telomerase inhibition. The volume is aimed at biochemists, molecular biologists, cancer researchers, and geneticists.
Inhibition Of Human Telomerase By Targeting Its Transitory Rna Dna Heteroduplex
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Author : Rawle Francis
language : en
Publisher:
Release Date : 2005
Inhibition Of Human Telomerase By Targeting Its Transitory Rna Dna Heteroduplex written by Rawle Francis and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2005 with RNA polymerases categories.
Telomerase is a target of intense scientific interest largely because of its implicated role in human carcinogenesis. The inactivation of this enzyme is widely believed to be a promising method to selectively destroy neoplastic cells, while leaving normal cells mostly unaffected. In this dissertation work, the inactivation of human telomerase by molecules based on nucleic acid intercalator structures is presented. The process of cell division shortens the distal portion of linear chromosomes (the telomere). Human telomerase, a special DNA polymerase which functions to maintain telomere length, is composed of RNA and protein subunits. Upon binding to its telomeric DNA substrate, a RNA/DNA heteroduplex is formed. The working hypothesis pursued here is that molecules which target this specific RNA/DNA heteroduplex will stabilize this structure and effectively stall telomerase polymerase activity. Since telomere maintenance is paramount for the survival of rapidly dividing cancer cells, the prevention of telomere maintenance, via inhibition of the telomerase enzyme, is a promising approach to cancer treatment. There are several other approaches to telomerase inhibition presented in the literature. However, targeting the RNA/DNA heteroduplex with the use of modified DNA intercalating agents is a novel and attractive approach to telomerase inhibition. A multifaceted methodology was undertaken to achieve the goal of producing specific inhibitors of human telomerase. First, commercially available nucleic acid intercalators were tested to obtain lead compounds with good inhibitory effect on telomerase activity. Secondly, utilizing techniques of enzyme kinetics, investigations were carried out to determine whether the telomerase RNA/DNA heteroduplex was the target of these lead compounds. Finally, the generation of more potent inhibitors of telomerase was attempted through the use of combinatorial peptide synthesis using lead intercalator(s) as the base structure. It was demonstrated in vitro, that more potent inhibitors of human telomerase could be developed by this approach. Using previously existing assay methods, in addition to original methods developed, relevant experiments were carried out to investigate the stated working hypothesis. During the course of these experiments many interesting observations were made, some of which were pursued and dealt with in these chapters.
Telomeres And Telomerase In Cancer
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Author : Keiko Hiyama
language : en
Publisher: Springer Science & Business Media
Release Date : 2009-03-18
Telomeres And Telomerase In Cancer written by Keiko Hiyama and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-03-18 with Medical categories.
Telomerase, an enzyme that maintains telomeres and endows eukaryotic cells with immortality, was first discovered in tetrahymena in 1985. In 1990s, it was proven that this enzyme also plays a key role in the infinite proliferation of human cancer cells. Now telomere and telomerase are widely accepted as important factors involved in cancer biology, and as promising diagnostic tools and therapeutic targets. Recently, role of telomerase in “cancer stem cells” has become another attractive story. Until now, there are several good books on telomere and telomerase focusing on biology in ciliates, yeasts, and mouse or basic sciences in human, providing basic scientists or students with updated knowledge.
The Molecular Regulation Of Telomeres And Telomerase
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Author : Craig Daniel Nicholls
language : en
Publisher:
Release Date : 2011
The Molecular Regulation Of Telomeres And Telomerase written by Craig Daniel Nicholls and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011 with categories.
Telomeres are nucleoprotein caps present at each chromosomal end that play a key role in maintaining genomic stability. Telomeres shorten with each cell division, eventually reaching a critical length at which cellular senescence or death pathways are activated. The enzyme telomerase overcomes this shortening through de novo synthesis of telomeric DNA, and telomerase activity is present at high levels in cancer and stem cells. Telomerase is highly regulated by extracellular and intracellular signals, with this regulation having important consequences for telomere homeostasis. This thesis primarily focuses on the novel role of the glycolytic enzyme glyceraldehyde-3- phosphate dehydrogenase (GAPDH) in the regulation of telomeres and telomerase. Chapter 3 demonstrates an interaction between single-stranded 3' C-rich telomeric overhangs and the N-terminal Rossman fold-containing NAD+ binding region of GAPDH. GAPDH is further revealed to inhibit telomerase activity in vitro and in cultured cells. This inhibition has been found to be dependent upon the C-terminal catalytic region of GAPDH. Furthermore, this chapter also demonstrates that nitric oxide modification of GAPDH impairs telomerase inhibition. Chapter 4 examines the relationship between the telomeric DNA binding activity of GAPDH and its telomerase inhibitory function. Several residues critical for mediating telomeric DNA binding were identified by site-directed mutagenesis and gel-shift assays. Expression of these GAPDH mutants in MCF7 breast cancer cells revealed that they retained the ability to inhibit telomerase, suggesting that telomeric DNA binding plays a role in positioning GAPDH on telomeres rather than inhibiting telomerase. However, the mutation K259N - located in a known protein-protein interaction region - abolishes telomerase inhibition and telomere shortening, demonstrating a critical role in telomerase inhibition for this region.This chapter also demonstrates for the first time an interaction between GAPDH and the telomerase RNA component hTERC, suggesting a switch between GAPDH binding of telomeric DNA and telomerase RNA. GAPDH specifically binds hTERC using identical components to those needed for the interaction with telomeric DNA. Furthermore, increased exogenous hTERC eliminates GAPDH-mediated telomerase inhibition. Recent studies from our laboratory have demonstrated that exogenous provision of several TGF[beta] superfamily cytokines can inhibit hTERT expression and telomerase activity. Chapter 5 focuses on the role in telomerase regulation played by the TGF[beta] superfamily type II receptors by inhibiting their action with siRNA or expression of dominant-negative (DN) proteins. Up-regulation of hTERT and telomerase activity resulted from receptor knockdown, confirming the telomerase inhibitory role for these receptors. However, longterm disruption of receptor signalling by stable expression of DN receptors resulted in telomerase inhibition in three of the four receptors examined. This data clearly demonstrates a role for TGF[beta] superfamily receptor signalling in telomerase regulation, though this regulation is likely complex in nature. In summary, this thesis investigates a new mechanismof telomere and telomerase regulation in GAPDH, while also furthering the understanding of the influence on telomerase activity by the TGF[beta] superfamily. The control of telomerase is important in the context of stem cell biology, cancer, and aging research and the findings from this thesis therefore have implications for all these fields.
Mechanism Of Telomerase Inhibition Using Small Inhibitory Rnas And Induction Of Breast Tumor Cell Sensitization
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Author :
language : en
Publisher:
Release Date : 2005
Mechanism Of Telomerase Inhibition Using Small Inhibitory Rnas And Induction Of Breast Tumor Cell Sensitization written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2005 with categories.
Telomerase, a ribonucleoprotein enzyme composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeres after cell divisions and is obligatory for continuous tumor cell proliferation as well as malignant progression of breast cancer cells. Telomerase is an attractive anti-cancer therapeutic agent because telomerase activity is present in over 90% of human breast cancers but is undetectable in most normal somatic cells. Traditional therapies (surgery, chemotherapy, radiotherapy, etc.) lack the ability to effectively control and cure breast cancer, primarily because residual cells are or become resistant to DNA damaging modalities including standard chemo- and radio-therapies. Since telomerase requires its associated hTR for repeat synthesis, we have chosen to use RNA interference as a method to inactivate hTR and hence telomerase. RNA interference (RNAI) has become a powerful tool for the analysis of gene function in that RNAI allows sequence specific inhibition of gene expression. Another protein we targeted is p21, which has long been established as a requirement for senescence. We wanted to further examine its relationship to senescence and apotosis, in an attempt to sensitize breast tumor cells more effectively.
Inhibition Of Telomerase From Human Ovarian Cancer Cells Via The Stabalization Of G Quadruplex Structures By Various Chemotheraputic Agents
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Author : Paul Edrick Schutt
language : en
Publisher:
Release Date : 2001
Inhibition Of Telomerase From Human Ovarian Cancer Cells Via The Stabalization Of G Quadruplex Structures By Various Chemotheraputic Agents written by Paul Edrick Schutt and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2001 with categories.
Telomerase Inhibition And Chemosensitization Of Prostate Cancer Cells
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Author :
language : en
Publisher:
Release Date : 2004
Telomerase Inhibition And Chemosensitization Of Prostate Cancer Cells written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004 with categories.
We hypothesize that telomerase inhibition (telomere shortening) can sensitize human tumor cells to existing anticancer drugs. During the period of the grant we made the following findings-: 1) 2'-methoxy ethyl oligonucleotides inhibit - -telomerase in prostate cancer cells, cause telomeres to shorten, and cause cell- proliferation to decrease; -2) Cell proliferation in culture is -more pronounced when cells are grown under conditions that mimic tumor growth; 3) Cell proliferation is dramatically reduced in a xenograft model using LNCAP cells, and 4) We did not observe significant synergy with standard chemotherapy agents. The ability of relatively short-term treatments with telomerase inhibitors to slow tumor growth in vivo suggests that telomerase inhibitors are a reasonable approach to prostate cancer therapy.
Mechanism Of Telomerase Inhibition Using A Small Inhibitory Rnas And Induction Of Breast Tumor Cell Sensitization
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Author :
language : en
Publisher:
Release Date : 2007
Mechanism Of Telomerase Inhibition Using A Small Inhibitory Rnas And Induction Of Breast Tumor Cell Sensitization written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007 with categories.
Telomerase, a ribonucleoprotein enzyme minimally composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeric repeats onto chromosome ends and is obligatory for continuous tumor cell proliferation, as well as malignant progression of breast cancer cells. Telomerase is an attractive anti-cancer therapeutic target because its activity is present in over 90% of human cancers, including more than 95% of breast carcinomas, but undetectable in most somatic cells. Traditional chemo- and radiotherapies lack the ability to effectively control and cure breast cancer, in part because residual cells are or become resistant to DNA damaging modalities. While various telomerase inhibition strategies cause cancer cells to undergo apoptosis or senescence, there is often a lag period between administration and biologic effect (Corey, 2002). Our goal in this study was to compare the efficacy of different telomerase inhibition strategies in concert with standard chemotherapeutic agents at triggering senescence and/or apoptosis in cultures of breast cancer cells. We hypothesized that telomerase inhibition strategies will sensitize breast cancer cells to traditional chemotherapies, potentially reducing the lag phase, allowing for more potent anti-tumor effects at lower doses, and therefore ultimately imparting less toxicity to the patient.
Mechanism Of Telomerase Inhibition Using Small Inibitory Rnas And Induction Of Breast Tumor Cell Sensitivity
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Author :
language : en
Publisher:
Release Date : 2007
Mechanism Of Telomerase Inhibition Using Small Inibitory Rnas And Induction Of Breast Tumor Cell Sensitivity written by and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2007 with categories.
Telomerase, a ribonucleoprotein enzyme composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeres after cell divisions and is obligatory for continuous tumor cell proliferation as well as malignant progression of breast cancer cells. Telomerase is an attractive anti-cancer therapeutic agent because telomerase activity is present in over 90% of human breast cancers but is undetectable in most normal somatic cells. Traditional therapies (surgery, chemotherapy, radiotherapy, etc.) lack the ability to effectively control and cure breast cancer, primarily because residual cells are or become resistant to DNA damaging modalities including standard chemo- and radio-therapies. Since telomerase requires its associated hTR for repeat synthesis, we have chosen to use RNA interference as a method to inactivate hTR and hence telomerase. RNA interference (RNAi) has become a powerful tool for the analysis of gene function in that RNAi allows sequence specific inhibition of gene expression. Another protein we targeted is p21, which has long been established as a requirement for senescence. We wanted to further examine its relationship to senescence and apotosis, in an attempt to sensitize breast tumor cells more effectively.
Telomerase Inhibition Telomere Shortening Cell Growth Suppression And Induction Of Apoptosis By Telomestatin In Childhood Neuroblastoma Cells
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Author : Nicolas Binz
language : en
Publisher:
Release Date : 2006
Telomerase Inhibition Telomere Shortening Cell Growth Suppression And Induction Of Apoptosis By Telomestatin In Childhood Neuroblastoma Cells written by Nicolas Binz and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2006 with categories.
