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Title: Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma through derepression of DUSP1 phosphatase and inhibition of ERK      
keywords:
Transcriptome or Gene expression
ID:
PRJNA167133
description:
We have investigated the role of the Notch pathway in the generation and maintenance of KrasG12V-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and Rbpj activities are both essential in the formation of NSCLCs. Interestingly, pharmacologic treatment of mice carrying endogenous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth and induces partial regression. Treated cancers show a reduction in Hes1 levels, reduced phosphorylated Erk, decreased proliferation and higher apoptosis. We demonstrate that HES1 directly binds and represses the promoter of DUSP1, a dual phosphatase with activity against phospho-ERK, and this repression is relieved by GSI treatment both in mouse and human NSCLCs. Our data provide proof for the in vivo therapeutic potential of γ-secretase inhibitors in primary NSCLCs and provide a mechanistic explanation for its therapeutical effect. Overall design: We have included 6 samples. 3 with vehicle and 3 with the gamma-secretase inhibitor DAPT and we compare both groups.
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA167133
authentication:
none
authorization:
none
ID:
pmid:22897852
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject