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research papers in aging & cancer

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Contact Shawn Holt, PhD for additional information and article copies: Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall Street, Sanger Hall, Richmond, Va 23298-0662.

Compton, S.A., L.W.Elmore, K.Haydu, C.K.Jackson-Cook and S.E.Holt. 2005. Induction of NOS-Dependent Telomere Shortening after Functional Inhibition of Hsp90 in Human Tumor Cells. Molecular and Cellular Biology, in press.

We find a direct connection between chaperones, NOS, and production of free radicals in directly damaging telomeres, firmly establishing chaperone inhibition as a potential therapeutic target for cancer.

McChesney,P.A., L.W.Elmore, and S.E.Holt. 2005. Vertebrate Marine Species as Model Systems for Studying Telomeres and Telomerase. Zebrafish, 1:349-355.

This paper establishes the newly defined role of fish as appropriate systems in which to study aging, cancer, tissue regeneration, and toxicological response, especially as they relate to telomeres and teomerase.

Elmore,L.W., X.Di, C.Dumur, S.E.Holt, and D.A.Gewirtz. 2005. Evasion of chemotherapy-induced senescence: implications for treatment response. Clin Cancer Res. 11:2637-43.

Here, we extensively characterize a clonal population of human breast cancer cells arising following a clinically relevant dose of Adriamycin and propose escape from DNA damage-induced senescence as a novel mechanism by which cancer cells evade conventional chemotherapies.

McChesney, P.A., L.W. Elmore, and S.E. Holt. 2002. Aging and oxidative damage: are telomeres the target? Comments on Theoretical Biology 7:295-313. 

This review argues for telomerase as sentinals for DNA damage during aging and oxidative stress. 

Elmore, L.W., C.W. Rehder, M. Di, P.A. McChesney, C.K. Jackson-Cook, D.A. Gewirtz, and S.E. Holt. 2002. Adriamycin-induced replicative senescence in tumor cells requires functional p53 and telomere dysfunction. J. Biol. Chem. 277:35509-35515.

We find that drug-induced senescence is the result of upregulation of the tumor suppressor, p53, and dysfunctional terlomeres rather than global terlomerase shortening. 

Elmore, L.W., K.C. Turner, L.S. Gollahon, M.R. Landon, C.K. Jackson-Cook, and S.E. Holt. 2002.Telomerase protects cancer-prone cells from chromosomal instability and spontaneous immortalization. Cancer Biology and Therapy 1:395-401.

Introduction of telomerase into normal cells that are predisposed to spontaneous immortalization prevents genomic rearrangements and the immortalization event, arguing for telomere maintenance as a tumor suppression mechanism. 

Elmore, L.W., H.L. Forsythe, A. Ferreira-Gonzalez, C.T. Garrett, G.M. Clark, and S.E. Holt. 2002. Real-Time Quantitative Analysis of Telomerase Activity in Breast Tumor Specimens using a Highly Specific and Sensitive Fluorescent-based Assay. Diagnostic Molecular Pathology 11: 177-185.

Development of a clinically friendly diagnostic telomerase activity assay using Real-Time quantitation, which increases sensitivity and accuracy. 

Harvey, S.A., K.O. Jensen, L.W. Elmore, and S.E. Holt. 2002. Pharmacological approaches to defining the role of chaperones in aging and prostate cancer progression. Cell Stress and Chaperones 7:230-234.

Discusses the role of chaperones as a molecular target for inhibiting telomerase during prostate cancer progression. 

Forsythe, H.L., K.O. Jensen, L.W. Elmore, and S.E. Holt. 2002. Ectopic expression of telomerase in human cells provides a growth advantage, extends proliferative life span, and rescues near senescent cells. International Journal of Oncology 20:1137-1143.

Overexpression of telomerase in normal dipoloid fibroblasts allows the cells to grow significantly faster, suggesting that less cells are falling out of the proliferative pool prematurely as in most normal cell populations without telomerase. 

A. Akalin, L.W. Elmore, H.L. Forsythe, B.A. Amaker, E.D. McCollum, P.S. Nelson, J.L. Ware, and S.E. Holt. 2001. A novel mechanism for chaperone-mediated telomerase regulation during prostate cancer progression. Cancer Research, 61:4791-4796.

An investigation of the relationship between the hsp90 chaperone complex and telomerase.

Forsythe, H.L., J.L. Jarvis, J.W. Turner, L.W. Elmore, and S.E. Holt. 2001. Stable association of hsp90 and p23 with human telomerase. J Biol. Chem. 276:15571-15574. 

We report here that the hsp70 chaperone also associates with hTERT in the absence of hTR and dissociates when telomerase is folded into its active state.

M.M. Ouellette, M. Liao, B-S Herbert, M. Johnson, S.E. Holt, H.S. Liss, J.W. Shay, & W.E. Wright. 2000. J Biol. Chem. 275:10072–10076.

Human fibroblasts expressing the catalytic component of human telomerase (hTERT) were followed for 250–400 population doublings.

V. M. Tesmer, L.P. Ford, S.E. Holt, B.C. Frank, X. YI, D.L. Aisner, M. Ouellette, J.W. Shay, & W.E. Wright. 1999. Two inactive fragments of the integral RNA cooperate to assemble active telomerase with the human protein catalytic subunit (hTERT) in vitro. Molecular and Cellular Biology 19:6207-16.

An investigation of what is required for efficient assembly of active telomerase in vitro. 

C.P. Morales, S.E. Holt, M. Ouellette, K.J. Kaur, Y. Yan, K.S. Wilson, M.A. White, W.E. Wright, & J.W. Shay. 1999. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nature Genetics 21:115-18.

An investigation of the long-term effects of forced expression of human telomerase catalytic component (hTERT) in normal human fibroblasts.

S.E. Holt, D.L. Aisner, J. Baur, V.M. Tesmer, M. Dy, M. Ouellette, J.B. Trager, G.B. Morin, D.O. Toft, J.W. Shay, W.E. Wright, & M.A. White. 1999. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes and Development 13:817-26.

A report showing that assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts.

A.G. Bodnar, , M. Ouellette, M. Frolkis, S.E. Holt, C-P Chiu, G.B. Morin, C.B., Harley, J.W. Shay, S. Lichtsteiner, W.E. Wright. 1998, January. Extension of lifespan by introduction of telomerase into normal human cells. Science, 79:349-52.

A test of the hypothesis that telomere shortening is the molecular clock that triggers senescence.

S.E. Holt, D.L. Aisner, J.W. Shay, & W.E. Wright. 1997. Lack of cell cycle regulation of telomerase activity in human cells. Proceedings of the National Academy of Sciences USA 94:10687-92.

A reexamination of conflicting reports concerning the cell cycle regulation of telomerase activity and its possible repression during quiescence and cell differentiation.

S.E. Holt, W.E. Wright, J.W. Shay. 1996. Regulation of telomerase activity in immortal cell lines. Molecular and Cellular Biology 16:2932-39.

A report on understanding the regulation of telomerase activity as a potential tool for the diagnosis and treatment of cancer.

Updated March 3, 2008