• Home
  • Search Results
  • Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.

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

Oncogene (2014-06-17)
S Kagawa, M Natsuizaka, K A Whelan, N Facompre, S Naganuma, S Ohashi, H Kinugasa, A M Egloff, D Basu, P A Gimotty, A J Klein-Szanto, A J Bass, K-K Wong, J A Diehl, A K Rustgi, H Nakagawa
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Hematoxylin
Sigma-Aldrich
BIS-TRIS, ≥98.0% (titration)
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
SAFC
BIS-TRIS, PharmaGrade, Manufactured under appropriate controls for use as a raw material in pharma or biopharmaceutical production, suitable for cell culture
Sigma-Aldrich
BIS-TRIS, BioXtra, ≥98.0% (titration)
Sigma-Aldrich
BIS-TRIS, BioUltra, ≥99.0% (NT)
Sigma-Aldrich
BIS-TRIS, BioPerformance Certified, suitable for cell culture, suitable for insect cell culture, ≥98.0%
Sigma-Aldrich
MISSION® esiRNA, targeting human CDKN1A
SAFC
BIS-TRIS, PharmaGrade, Manufactured under appropriate controls for use as a raw material in pharma or biopharmaceutical production., suitable for cell culture
Sigma-Aldrich
MISSION® esiRNA, targeting human RBM14
Sigma-Aldrich
MISSION® esiRNA, targeting human SLC12A9
Sigma-Aldrich
MISSION® esiRNA, targeting human RBM4, RBM14-RBM4

Social Media

LinkedIn icon
Twitter icon
Facebook Icon
Instagram Icon

Merck

Research. Development. Production.

We are a leading supplier to the global Life Science industry with solutions and services for research, biotechnology development and production, and pharmaceutical drug therapy development and production.

© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

Reproduction of any materials from the site is strictly forbidden without permission.