title: EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis.
abstract: Telomerase plays an important role during immortalization and malignant transformation as crucial steps in the development of human cancer. In a cellular model of oral-esophageal carcinogenesis, recapitulating the human disease, immortalization occurred independent of the activation of telomerase but through the recombination-based alternative lengthening of telomeres (ALT). In this stepwise model, additional overexpression of EGFR led to in vitro transformation and activation of telomerase with homogeneous telomere elongation in already immortalized oral squamous epithelial cells (OKF6-D1_dnp53). More interestingly, EGFR overexpression activated the PI3K/AKT pathway. This strongly suggested a role for telomerase in tumor progression in addition to just elongating telomeres and inferring an immortalized state. Therefore, we sought to identify the regulatory mechanisms involved in this activation of telomerase and in vitro transformation induced by EGFR. In the present study we demonstrate that telomerase expression and activity are induced through both direct phosphorylation of hTERT by phospho-AKT as well as PI3K-dependent transcriptional regulation involving Hif1-alpha as a key transcription factor. Furthermore, EGFR overexpression enhanced cell cycle progression and proliferation via phosphorylation and translocation of p21. Whereas immortalization was induced by ALT, in vitro transformation was associated with telomerase activation, supporting an additional role for telomerase in tumor progression besides elongating telomeres.
authors.affiliation: Department of Medicine, Institute for Molecular Medicine and Cell Research, Tumorzentrum Ludwig Heilmeyer-Comprehensive Cancer Center Freiburg, Amsterdam, the Netherlands.
authors.forename: Steffen
authors.initials: S
authors.lastname: Heeg
authors.forename: Nina
authors.initials: N
authors.lastname: Hirt
authors.forename: Angela
authors.initials: A
authors.lastname: Queisser
authors.forename: Hannah
authors.initials: H
authors.lastname: Schmieg
authors.forename: Michaela
authors.initials: M
authors.lastname: Thaler
authors.forename: Heike
authors.initials: H
authors.lastname: Kunert
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: Gitta
authors.initials: G
authors.lastname: Goessel
authors.forename: Alexander
authors.initials: A
authors.lastname: von Werder
authors.forename: Jan
authors.initials: J
authors.lastname: Harder
authors.forename: Roderick
authors.initials: R
authors.lastname: Beijersbergen
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Opitz
mesh_terms: D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D019098:Telomerase / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase