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Loss of Notch1-dependent p21(Waf1/Cip1) expression influences the Notch1 outcome in tumorigenesis.
- Source :
-
Cell cycle (Georgetown, Tex.) [Cell Cycle] 2014; Vol. 13 (13), pp. 2046-55. Date of Electronic Publication: 2014 May 06. - Publication Year :
- 2014
-
Abstract
- Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor-suppressor and oncogenic components. In this study we investigated the effects of reactive oxygen species (ROS) on Notch1 signaling outcome in keratinocyte biology. We demonstrate that Notch1 function contributes to the arsenic-induced keratinocyte transformation. We found that acute exposure to arsenite increases oxidative stress and inhibits proliferation of keratinocyte cells by upregulation of p21(waf1/Cip1). The necessity of p21(waf1/Cip1) for arsenite-induced cell death was demonstrated by targeted downregulation of p21(waf1/Cip1) by using RNA interference. We further demonstrated that on acute exposure to arsenite, p21(waf1/Cip1) is upregulated and Notch1 downmodulated, whereas on chronic exposure to arsenite, malignant progression of arsenite-treated keratinocytes cells was accompanied by regained expression and activity of Notch1. Notch1 activity in arsenite-transformed keratinocytes inhibits arsenite-induced upregulation of p21(waf1/Cip1) by sustaining c-myc expression. We further demonstrated that c-myc collaborates with Nrf2, a key regulator for the maintenance of redox homeostasis, to promote metabolic activities that support cell proliferation and cytoprotection. Therefore, Notch1-mediated repression of p21(waf1/Cip1) expression results in the inhibition of cell death and keratinocytes transformation. Our results not only demonstrate that sustained Notch1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect, but also may provide mechanistic insights into the molecular aspects that determine whether Notch signaling will be either oncogenic or tumor suppressive.
- Subjects :
- Apoptosis drug effects
Arsenites toxicity
Carcinogenesis drug effects
Carcinogenesis pathology
Cell Cycle Proteins metabolism
Cell Line
Cell Proliferation drug effects
Cyclin-Dependent Kinase Inhibitor p21 metabolism
F-Box Proteins metabolism
F-Box-WD Repeat-Containing Protein 7
Humans
Keratinocytes drug effects
Keratinocytes pathology
MicroRNAs metabolism
NF-E2-Related Factor 2 metabolism
Oxidative Stress drug effects
Proto-Oncogene Proteins c-myc genetics
Reactive Oxygen Species metabolism
Receptor, Notch1 genetics
Ubiquitin-Protein Ligases metabolism
Carcinogenesis metabolism
Cyclin-Dependent Kinase Inhibitor p21 genetics
Receptor, Notch1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1551-4005
- Volume :
- 13
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Cell cycle (Georgetown, Tex.)
- Publication Type :
- Academic Journal
- Accession number :
- 24801890
- Full Text :
- https://doi.org/10.4161/cc.29079