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You searched for subject:(hTERT regulation). Showing records 1 – 3 of 3 total matches.

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1. Linne, Hannah Louise. Investigating telomerase regulation in human breast cancer cells : a search for telomerase repressor sequences localised to chromosome 3P.

Degree: PhD, 2015, Brunel University

Cellular immortality is one of the ten hallmarks of human cancer and has been shown to be an essential prerequisite for malignant progression (Hanahan and Weinberg., 2011, Newbold et al., 1982, Newbold and Overell., 1983). In contrast, normal human somatic cells proliferate for a limited number of population doublings before entering permanent growth arrest known as replicative senescence. This is thought to be due to the progressive shortening of telomeric sequences with each round of cell division. Over 90% of human tumours, but not the majority of human somatic cells, have been found to express telomerase activity (Kim et al., 1994). The rate-limiting component of the human telomerase enzyme is the telomerase reverse transcriptase subunit, which is encoded by the hTERT gene. Transfection of hTERT cDNA into normal human fibroblasts and epithelial cells may sometimes be sufficient to confer cellular immortality (Newbold., 2005, Stampfer and Yaswen., 2002). Therefore, de-repression of hTERT and telomerase re-activation are thought to be critical events in human carcinogenesis and is the predominant mechanism by which cancer cells maintain their proliferative capacity. Previously, our group has shown that introduction of a normal, intact copy of human chromosome 3 into the 21NT primary breast cancer cell line by microcell-mediated monochromosome transfer (MMCT), is associated with strong telomerase repression and induction of cell growth arrest within the majority of hybrid clones (Cuthbert et al., 1999). Structural mapping of chromosome 3 within telomerase-positive revertent clones revealed two regions of deletion: 3p21.3-p22 and 3p12-p21.1, thought to harbour the putative telomerase repressor sequence(s). Subsequent studies showed that the chromosome 3p-encoded telomerase repressor sequence(s) mediates its function by means of transcriptional silencing of hTERT, in part, through chromatin remodelling of two sites within intron 2 of the hTERT gene (Ducrest et al., 2001, Szutorisz et al., 2003). Attempts to achieve positional cloning of hTERT repressor sequences on chromosome 3p identified two interesting candidates; the histone methyltransferase SETD2 and an adjacent long non-coding RNA (lncRNA) sequence known as FLJ/KIF9-AS1 (Dr. T. Roberts, unpublished data). Through MMCT-mediated introduction of intact chromosomes 3 and 17 into the 21NT cell line, I have demonstrated that at least two as yet unidentified telomerase repressor sequences (one located on each of these two normal chromosomes) may function to repress telomerase activity within the same breast cancer cell line, which suggests that multiple, independent telomerase regulatory pathways may be inactivated within the same cancer type. Furthermore, by examining the consequences of forced SETD2 and FLJ expression within the 21NT cell line, together with siRNA-mediated knockdown of SETD2 within a single telomerase-repressed 21NT-chromosome 3 hybrid, I have provided evidence to show that neither of these two candidate genes may function as a regulator of hTERT…

Subjects/Keywords: 616.99; hTERT regulation; Immortalisation; Molecular changes associated with cellular immortalisation

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APA (6th Edition):

Linne, H. L. (2015). Investigating telomerase regulation in human breast cancer cells : a search for telomerase repressor sequences localised to chromosome 3P. (Doctoral Dissertation). Brunel University. Retrieved from http://bura.brunel.ac.uk/handle/2438/11620 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675877

Chicago Manual of Style (16th Edition):

Linne, Hannah Louise. “Investigating telomerase regulation in human breast cancer cells : a search for telomerase repressor sequences localised to chromosome 3P.” 2015. Doctoral Dissertation, Brunel University. Accessed November 18, 2019. http://bura.brunel.ac.uk/handle/2438/11620 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675877.

MLA Handbook (7th Edition):

Linne, Hannah Louise. “Investigating telomerase regulation in human breast cancer cells : a search for telomerase repressor sequences localised to chromosome 3P.” 2015. Web. 18 Nov 2019.

Vancouver:

Linne HL. Investigating telomerase regulation in human breast cancer cells : a search for telomerase repressor sequences localised to chromosome 3P. [Internet] [Doctoral dissertation]. Brunel University; 2015. [cited 2019 Nov 18]. Available from: http://bura.brunel.ac.uk/handle/2438/11620 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675877.

Council of Science Editors:

Linne HL. Investigating telomerase regulation in human breast cancer cells : a search for telomerase repressor sequences localised to chromosome 3P. [Doctoral Dissertation]. Brunel University; 2015. Available from: http://bura.brunel.ac.uk/handle/2438/11620 ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675877


Virginia Commonwealth University

2. Sachs, Patrick. REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING.

Degree: PhD, Human Genetics, 2010, Virginia Commonwealth University

A great need exists for an abundant, easily accessible source of patient-specific cells that will function for use in regenerative medicine. One promising source is the adult stem cell derived from adipose tissue (ASCs). Isolated from waste lipoaspiration, these cells could serve as a readily available source for the regeneration of damaged tissues. To further define the biology of ASCs, we have isolated multiple cell strains from different adipose tissue sources, indicating wide-spread distribution in the body. We find that a widely used set of cell surface markers fail to distinguish ASCs from normal fibroblasts. However, our ASC isolations are multipotent while fibroblasts show no differentiation potential. In further contrast to fibroblasts, these cells also show expression of genes associated with pluripotent cells, Oct-4, SOX2, and NANOG. Together, our data suggest that while the cell surface profile of ASCs do not distinguish them from normal fibroblasts and their lack of telomerase shows their limited proliferation capacity, the expression of genes closely linked to pluripotency and their differentiation capacity clearly define ASCs as multipotent stem cells. iPS cells are another promising cell type for tissue regeneration, due to their expression of hTERT and their capacity to differentiate into all three germ layers. Interestingly, telomerase is activated during the induction process, accomplished by the exogenous expression of four genes in normal, non-hTERT-expressing fibroblasts. To elucidate the mechanisms behind this activation, we examined the overexpression of these four factors in BJ fibroblasts and ASCs, which resulted in undetectable hTERT expression. We then demonstrated a lack of an acetylated histone H3K9 with the opposing di-methylation, indicative of a closed chromatin state at the hTERT promoter. Subsequent treatment of cells with TSA alone showed an upregulation of hTERT mRNA without telomerase activity. However, telomerase activity was found when ASCs, but not BJs were treated with TSA and all four factors, indicating differential regulation of hTERT in cells of similar mesenchymal origins. Our data suggest that while hTERT’s expression is universally dependent on the presence of a relaxed chromatin state and sufficient transactivating factors, other cell to cell differences can prevent its expression. Advisors/Committee Members: Shawn Holt.

Subjects/Keywords: Telomerase regulation; hTERT; iPS; Induced pluripotent stem cells; Medical Genetics; Medical Sciences; Medicine and Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Sachs, P. (2010). REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://scholarscompass.vcu.edu/etd/40

Chicago Manual of Style (16th Edition):

Sachs, Patrick. “REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING.” 2010. Doctoral Dissertation, Virginia Commonwealth University. Accessed November 18, 2019. https://scholarscompass.vcu.edu/etd/40.

MLA Handbook (7th Edition):

Sachs, Patrick. “REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING.” 2010. Web. 18 Nov 2019.

Vancouver:

Sachs P. REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2010. [cited 2019 Nov 18]. Available from: https://scholarscompass.vcu.edu/etd/40.

Council of Science Editors:

Sachs P. REGULATION OF TELOMERASE EXPRESSION IN STEM CELL REPROGRAMMING. [Doctoral Dissertation]. Virginia Commonwealth University; 2010. Available from: https://scholarscompass.vcu.edu/etd/40


Virginia Commonwealth University

3. Jensen, Keith Douglas Ostergaard. Dual Regulation of Telomerase Activity By HSF1 And Its Role in Prostate Cancer Progression.

Degree: PhD, Human Genetics, 2006, Virginia Commonwealth University

It has been shown that the key components of the hsp90 chaperone complex, including hsp90, p23, hsp70, hsp40, and HOP (p60), associate with telomerase; however, their specific roles in telomerase function and tumor progression have not yet been defined. HSF1, the primary mammalian heat shock protein transcription factor, may affect telomerase activity and transformation by regulating the expression of several hsp90 chaperone complex proteins in response to stress as well as regulating the transcription of hTERT, the protein subunit of telomerase.In our in vitro model of prostate cancer progression, as cells progress from immortal but non-tumorigenic (P69) to tumorigenic (M2182) and eventually metastatic (M12) capabilities, both telomerase activity and global chaperone protein levels increase. Our hypothesis is that HSF1 affects telomerase activity directly at the level of transcription and indirectly at the protein level via its regulation of proteins of the hsp90 chaperone complex. Furthermore, upregulation of HSF1 and/or members of the hsp90 chaperone complex directly contribute to prostate cell transformation and that introduction of chaperone-related genes will convert non-tumorigenic prostate cells to a tumorigenic state.We have shown that ectopic overexpression of HSF1 induces increased expression of endogenous hsp90 in P69 cells. Furthermore, telomerase activity in the overexpressing HSF1 cell lines is increased as well and is the end result of two disparate, yet ultimately cooperating pathways. However, the increased telomerase activity does not correlate with increased tumorigenicity.In conjunction with this study, we have overexpressed hTERT in the P69 cell lines and found that telomerase activity is markedly increased in the absence of chaperone upregulation. We propose that the demand for increased folding and stability of the exogenous hTERT leads to a recruitment of telomerase associated chaperone proteins, which can be measured by increased activity after immunoprecipitations and nuclear translocation of hsp90 chaperone complex proteins.Taken together, these projects indicate a significant role for HSF1 and the hsp90 chaperone complex proteins on telomerase activity, and provide evidence that each may be a viable target for therapeutic intervention. Advisors/Committee Members: Dr. Shawn E. Holt.

Subjects/Keywords: tumor; protein; cancer; chromosome; cell regulation; hTERT; Medical Genetics; Medical Sciences; Medicine and Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Jensen, K. D. O. (2006). Dual Regulation of Telomerase Activity By HSF1 And Its Role in Prostate Cancer Progression. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://scholarscompass.vcu.edu/etd/971

Chicago Manual of Style (16th Edition):

Jensen, Keith Douglas Ostergaard. “Dual Regulation of Telomerase Activity By HSF1 And Its Role in Prostate Cancer Progression.” 2006. Doctoral Dissertation, Virginia Commonwealth University. Accessed November 18, 2019. https://scholarscompass.vcu.edu/etd/971.

MLA Handbook (7th Edition):

Jensen, Keith Douglas Ostergaard. “Dual Regulation of Telomerase Activity By HSF1 And Its Role in Prostate Cancer Progression.” 2006. Web. 18 Nov 2019.

Vancouver:

Jensen KDO. Dual Regulation of Telomerase Activity By HSF1 And Its Role in Prostate Cancer Progression. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2006. [cited 2019 Nov 18]. Available from: https://scholarscompass.vcu.edu/etd/971.

Council of Science Editors:

Jensen KDO. Dual Regulation of Telomerase Activity By HSF1 And Its Role in Prostate Cancer Progression. [Doctoral Dissertation]. Virginia Commonwealth University; 2006. Available from: https://scholarscompass.vcu.edu/etd/971

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