title: Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.
abstract: Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor-suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor-suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16(INK4A)-Rb pathway. Loss of p16(INK4A) or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as transforming growth factor-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor-suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kagawa
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [3] Department of Gastroenterology and Hepatology, Hokkaido University, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Natsuizaka
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Whelan
authors.affiliation: 1] Departments of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA [2] Philadelphia VA Medical Center, Philadelphia, PA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Facompre
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [3] Department of Pathology, Kochi University Medical School, Kochi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Naganuma
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [3] Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [3] Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kinugasa
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Egloff
authors.affiliation: 1] Departments of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA [2] Philadelphia VA Medical Center, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Basu
authors.affiliation: 1] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [2] Division of Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, MA, USA [2] Division of Cellular and Molecular Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: 1] Department of Medicine, Harvard Medical School, Boston, MA, USA [2] Division of Cellular and Molecular Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: K-K
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [3] Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: 1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Nakagawa
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D016922:Cellular Senescence; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D010766:Phosphorylation; D051881:Receptor, Notch1 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D014764:Viral Proteins