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You searched for subject:(Telomerase Inhibitors 60). Showing records 1 – 2 of 2 total matches.

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1. Phipps, Sharla Marion Ostein. Genetic and epigenetic modulation of telomerase activity in development and disease.

Degree: PhD, 2007, University of Alabama – Birmingham

The end replication problem of linear chromosomes leads to the erosion of telomeric DNA with each cell division. A mechanism to counteract telomeric attrition involves the activity of the specialized ribonucleoprotein telomerase. Expression of the catalytic subunit of telomerase, hTERT, is tightly regulated and this regulation is achieved through both genetic and epigenetic mechanisms. Activators such as c-MYC and SP1 and repressors such as MAD1, Menin, and p53 mediate hTERT transcription. Epigenetic control mediated by DNA methylation and histone modifications such as methylation and acetylation can reversibly and potently regulate telomerase activity. Not only is there synergism between the epigenetic regulatory mechanisms of DNA methylation and histone acetylation, there is also significant interaction between the genetic and epigenetic methods of hTERT gene regulation. Understanding mechanisms that govern hTERT expression can lead to insights into cellular processes such as embryonic development, differentiation, cancer progression, and aging because of the integral role of telomerase activity in these occurrences. The studies outlined in this dissertation attempt to elucidate some of the mechanisms modulating hTERT transcription and telomerase activity in the initiation of cellular differentiation and in a human breast cancer model. To this end, we have developed a novel model system to investigate differentially-expressed genes during the course of in vitro human embryonic stem cell differentiation. We have also presented data showing a stronger correlation between hTERT expression and expression of the epigenetic regulators DNMT3a and DNMT3b than between other epigenetic regulatory mechanisms. In the breast cancer model, we have investigated the effects of prolonged all-trans retinoic acid exposure on these cells and have demonstrated changes in cellular morphology, growth rate, and anchorage-independence. We have also observed that this retinoid slowly decreases telomerase activity, possibly due to the epigenetic changes induced at the hTERT promoter. The result of these investigations is a deeper comprehension of the complexities involved in telomerase regulation in normal regulated and unregulated cancer systems. This understanding gives insight into the early events of aging and telomere shortening and could lead to improved anti-cancer therapeutics that utilize modes of hTERT down-regulation to stop the growth of telomerase-addicted neoplastic cells.

xii, 120 p. : ill. (chiefly col.), digital, PDF file.

Biology

Natural Sciences and Mathematics

Telomerase Breast cancer ATRA Human embryonic stem cells hTERT Epigenetics

UNRESTRICTED

Advisors/Committee Members: Tollefsbol, Trygve O., Ghanta, Vithal K.<br>, Ruppert, J. Michael <br>, Strong, Theresa V.<br>, Watson, R. Douglas.

Subjects/Keywords: Telomerase  – Physiological effect <; br>; Telomerase  – Inhibitors <; br>; Genetic regulation <; br>; Enzymes  – Regulation <; br>; Genetic transcription <; br>; Reverse transcriptase <; br>; Breast  – Cancer  – Genetic aspects <; br>; Tretinoin  – Physiological effect <; br>; Epigenesis.

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

APA (6th Edition):

Phipps, S. M. O. (2007). Genetic and epigenetic modulation of telomerase activity in development and disease. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,260

Chicago Manual of Style (16th Edition):

Phipps, Sharla Marion Ostein. “Genetic and epigenetic modulation of telomerase activity in development and disease.” 2007. Doctoral Dissertation, University of Alabama – Birmingham. Accessed September 17, 2019. http://contentdm.mhsl.uab.edu/u?/etd,260.

MLA Handbook (7th Edition):

Phipps, Sharla Marion Ostein. “Genetic and epigenetic modulation of telomerase activity in development and disease.” 2007. Web. 17 Sep 2019.

Vancouver:

Phipps SMO. Genetic and epigenetic modulation of telomerase activity in development and disease. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2007. [cited 2019 Sep 17]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,260.

Council of Science Editors:

Phipps SMO. Genetic and epigenetic modulation of telomerase activity in development and disease. [Doctoral Dissertation]. University of Alabama – Birmingham; 2007. Available from: http://contentdm.mhsl.uab.edu/u?/etd,260

2. Berletch, Joel Bradford. Green tea polyphenols are associated with changes in genetic and epigenetic anti-cancer mechanisms in vitro and in vivo.

Degree: PhD, 2007, University of Alabama – Birmingham

Human chromosomes are protected from degradation associated with cell division by hexameric repeats of 5’-TTAGGG-3’ termed telomeres. During cellular replication human chromosomes undergo the loss of up to 300 bp of DNA with each division, reaching a critical length which leads to senescence and apoptosis. Most cancer cells bypass this lifespan regulatory mechanism by the expression of telomerase, a protein complex that adds telomeres through the reverse transcriptase activity of its catalytic subunit, hTERT. Approximatly 90% of all cancers express the hTERT gene making it an attractive target for novel cancer therapies. The objective of this dissertation was to help identify the mechanism by which (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, can inhibit cancer cell growth and proliferation both in vitro and in vivo. Major discoveries of this work include: 1) exposure to EGCG leads to reduced cellular proliferation and an induction of apoptosis in MCF-7 breast cancer cells and HL60 promyelocytic leukemia cells; 2) EGCG treatment leads to hTERT down-regulation in MCF-7 cells but not in HL60 cells; 3) the ability of EGCG to reduce HL60 growth may not be due to epigenetic mechanisms; 4) MCF-7 cells grown in the presence of EGCG showed a time-dependent demethylation of the key E2F-1 binding sites in the hTERT promoter and an increased capacity to bind E2F-1; and 5) histone acetylation at the hTERT promoter region was decreased in MCF-7 cells. Additional studies preformed on human lung cancer xenografts revealed that intraperitoneal (i.p.) injection of EGCG can decrease methylation at the hTERT promoter in these tumors. EGCG was also shown to inhibit DNMT1 protein expression in treated tumor samples. Future studies further illustrating the epigenetic and genetic mechanisms involved in the anti-cancer mechanisms of EGCG in vivo are needed. Investigation into histone alterations after xenograft treatment is essential to understanding the epigenetic processes associated with EGCG treatment. In conclusion, EGCG has been shown to be an attractive natural compound with the ability to induce genetic and epigenetic pathways to both inhibit cancer cell proliferation and actively kill cancer cells by inducing apoptosis.

xii, 95 p. : ill. (some col.), digital, PDF file.

Biology

Natural Sciences and Mathematics

Epigenetics EGCG Telomerase DNA methylation Histone acetylation Green tea

UNRESTRICTED

Advisors/Committee Members: Tollefsbol, Trygve O., Elgavish, Ada <br>, Ghanta, Vithal <br>, Hsu, Hui-Chen <br>, Wibbels, Thane.

Subjects/Keywords: Antineoplastic agents <; br>; Cancer  – Genetic aspects <; br>; Gene targeting <; br>; Cancer cells  – Growth  – Regulation <; br>; Telomerase  – Inhibitors <; br>; Catechin  – Physiological effect <; br>; Green tea  – Physiological effect.

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

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

APA (6th Edition):

Berletch, J. B. (2007). Green tea polyphenols are associated with changes in genetic and epigenetic anti-cancer mechanisms in vitro and in vivo. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,174

Chicago Manual of Style (16th Edition):

Berletch, Joel Bradford. “Green tea polyphenols are associated with changes in genetic and epigenetic anti-cancer mechanisms in vitro and in vivo.” 2007. Doctoral Dissertation, University of Alabama – Birmingham. Accessed September 17, 2019. http://contentdm.mhsl.uab.edu/u?/etd,174.

MLA Handbook (7th Edition):

Berletch, Joel Bradford. “Green tea polyphenols are associated with changes in genetic and epigenetic anti-cancer mechanisms in vitro and in vivo.” 2007. Web. 17 Sep 2019.

Vancouver:

Berletch JB. Green tea polyphenols are associated with changes in genetic and epigenetic anti-cancer mechanisms in vitro and in vivo. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2007. [cited 2019 Sep 17]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,174.

Council of Science Editors:

Berletch JB. Green tea polyphenols are associated with changes in genetic and epigenetic anti-cancer mechanisms in vitro and in vivo. [Doctoral Dissertation]. University of Alabama – Birmingham; 2007. Available from: http://contentdm.mhsl.uab.edu/u?/etd,174

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