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Carcinogenesis Advance Access published online on June 15, 2005
Carcinogenesis, doi:10.1093/carcin/bgi153
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received December 22, 2004
Revised May 17, 2005
Accepted June 7, 2005

CANCER BIOLOGY

Differential transcriptional regulation of human telomerase in a cellular model representing important genetic alterations in esophageal squamous carcinogenesis

Michael Quante 1, Steffen Heeg 1, Alexander von Werder 1, Gitta Goessel 1, Christine Fulda 1, Michaela Doebele 1, Hiroshi Nakagawa 2, Roderick Beijersbergen 3, Hubert E. Blum 1, and Oliver G. Opitz 1*

1 Department of Medicine, University of Freiburg, Freiburg, Germany
2 Gastroenterology Division, University of Pennsylvania, Philadelphia, PA, USA
3 Netherlands Cancer Institute, Amsterdam, NL

* To whom correspondence should be addressed.
Oliver G. Opitz, E-mail: opitz{at}med1.ukl.uni-freiburg.de


  Abstract

Telomerase activity is observed in about 90% of human cancer including esophageal squamous cell cancer. Normal somatic cells do not display telomerase activity on a regular basis. The major mechanism to regulate telomerase activity in human cells is the transcriptional control of the catalytic subunit, the human reverse transcriptase gene hTERT. However, the manner in which telomerase activity is regulated during malignant transformation and whether this regulation is influenced by single genetic alterations important in this process is not well understood. In this study we investigated the transcriptional regulation and activity of human telomerase in a cellular model representing important known genetic alterations observed in esophageal cancer. We characterized the respective cells with regard to their telomere biology and telomerase expression, transcriptional regulation using promoter- as well as EMSA-analyses and their promoter methylation status. We could demonstrate that telomerase expression and subsequent activity is differentially regulated in the progression from normal esophageal epithelial cells to genetically defined esophageal cells harboring a specific genetic alteration frequently found in esophageal cancer and compared those changes to esophageal cancer cells. Whereas primary esophageal cells are mainly regulated by Sp1, in cells harboring a genetic alteration as cyclin D1 overexpression other transcription factors like E2F and c-myc as well as promoter methylation influence hTERT transcription. This model demonstrates that the transcriptional regulation of telomerase is influenced by a given genetic alteration important in esophageal cancer and therefore provides new insight in telomerase regulation during carcinogenesis.

Keywords: telomerase; transcriptional regulation; esophagus; keratinocytes; cyclin D1; p53.
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