Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities
| Autor: | Mitsuteru Natsuizaka, Phyllis A. Gimotty, Devraj Basu, Andres J. Klein-Szanto, Nicole D. Facompre, Ann Marie Egloff, Shingo Kagawa, Anil K. Rustgi, Seiji Naganuma, J A Diehl, Kelly A. Whelan, Kwok K. Wong, Shinya Ohashi, Hiroshi Nakagawa, Hideaki Kinugasa, Adam J. Bass |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Senescence
Keratinocytes squamous cell carcinoma Cancer Research Cell signaling HPV Cell cycle checkpoint Notch senescence Esophageal Neoplasms Notch signaling pathway Endogeny p16 Cell morphology Retinoblastoma Protein Article Viral Proteins Esophagus Transforming Growth Factor beta Genetics Humans Phosphorylation Receptor Notch1 Rb Molecular Biology Cells Cultured Cellular Senescence E7 biology Retinoblastoma protein Cell Cycle Checkpoints Cell Transformation Viral Cell biology biology.protein Cancer research Carcinoma Squamous Cell Esophageal Squamous Cell Carcinoma Cell aging Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|