Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases

Details

Serval ID
serval:BIB_8E081E9B53E4
Type
Article: article from journal or magazin.
Collection
Publications
Title
Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases
Journal
Genes and Development
Author(s)
Lefort  K., Mandinova  A., Ostano  P., Kolev  V., Calpini  V., Kolfschoten  I., Devgan  V., Lieb  J., Raffoul  W., Hohl  D., Neel  V., Garlick  J., Chiorino  G., Dotto  G. P.
ISSN
0890-9369 (Print)
Publication state
Published
Issued date
03/2007
Volume
21
Number
5
Pages
562-77
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: Mar 1
Abstract
Little is known about the regulation and function of the Notch1 gene in negative control of human tumors. Here we show that Notch1 gene expression and activity are substantially down-modulated in keratinocyte cancer cell lines and tumors, with expression of this gene being under p53 control in these cells. Genetic suppression of Notch signaling in primary human keratinocytes is sufficient, together with activated ras, to cause aggressive squamous cell carcinoma formation. Similar tumor-promoting effects are also caused by in vivo treatment of mice, grafted with keratinocytes expressing oncogenic ras alone, with a pharmacological inhibitor of endogenous Notch signaling. These effects are linked with a lesser commitment of keratinocytes to differentiation, an expansion of stem cell populations, and a mechanism involving up-regulation of ROCK1/2 and MRCKalpha kinases, two key effectors of small Rho GTPases previously implicated in neoplastic progression. Thus, the Notch1 gene is a p53 target with a role in human tumor suppression through negative regulation of Rho effectors.
Keywords
Animals Carcinoma, Squamous Cell/*genetics/metabolism/pathology Cell Culture Techniques Cell Differentiation Cell Line, Tumor Down-Regulation *Genes, Tumor Suppressor Humans Intracellular Signaling Peptides and Proteins/*metabolism Keratinocytes/cytology/*metabolism Mice Protein-Serine-Threonine Kinases/*metabolism Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors RNA, Small Interfering Receptor, Notch1/*genetics/metabolism Signal Transduction Skin Neoplasms/genetics/metabolism/pathology Stem Cells/cytology Tumor Suppressor Protein p53/*metabolism Tumor Suppressor Proteins/genetics/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:59
Last modification date
20/08/2019 15:51
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