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Oncogene. 2015 Apr 30;34(18):2347-59. doi: 10.1038/onc.2014.169. Epub 2014 Jun 16.

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.

Author information

1
1] Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA [2] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
2
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.
3
1] Departments of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA [2] Philadelphia VA Medical Center, Philadelphia, PA, USA.
4
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.
5
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.
6
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.
7
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
8
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.
9
Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
10
1] Department of Medicine, Harvard Medical School, Boston, MA, USA [2] Division of Cellular and Molecular Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
11
1] Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
12
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.

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.

PMID:
24931169
PMCID:
PMC4268095
DOI:
10.1038/onc.2014.169
[Indexed for MEDLINE]
Free PMC Article

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