title: Differential transcriptional regulation of human telomerase in a cellular model representing important genetic alterations in esophageal squamous carcinogenesis.
abstract: Telomerase activity is observed in approximately 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 are 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 electrophoretic mobility shift assay--analyses and their promoter methylation status. We could demonstrate that telomerase expression and subsequent activity are 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 with 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.
authors.affiliation: Department of Medicine and Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: Steffen
authors.initials: S
authors.lastname: Heeg
authors.forename: Alexander
authors.initials: A
authors.lastname: von Werder
authors.forename: Gitta
authors.initials: G
authors.lastname: Goessel
authors.forename: Christine
authors.initials: C
authors.lastname: Fulda
authors.forename: Michaela
authors.initials: M
authors.lastname: Doebele
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Roderick
authors.initials: R
authors.lastname: Beijersbergen
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Opitz
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D016329:Sp1 Transcription Factor; D019098:Telomerase