Linked Life Data

18098337

Source:http://linkedlifedata.com/resource/pubmed/id/18098337

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-1-17
pubmed:abstractText
BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. These two molecules are prone to mutations in sporadic microsatellite unstable (MSI) colorectal carcinomas (CRC) and BRAF V600E mutations are inversely associated with oncogenic KRAS mutations. The biological significance of BRAF V600E oncogenic activation is not well established in this type of tumour. We aimed to study proliferation and survival effects induced by BRAF inhibition in MSI CRC cell lines harbouring distinct genetic backgrounds (BRAF V600E or KRAS G13D). Suppression of BRAF in BRAF V600E MSI CRC cell lines by RNA interference significantly inhibited proliferation and induced apoptosis, as demonstrated by BrdU incorporation and TUNEL assay, respectively. No significant differences were seen in proliferation and apoptosis, in cell lines harbouring KRAS G13D, after BRAF inhibition. We further analysed proliferation-associated molecules (pERK1/2, cyclin D1, p27 Kip1) and apoptosis-associated molecules (Bcl-2, Bax, pAkt, pBad, XIAP) in all cell lines. After BRAF down-regulation, we found a more pronounced decrease in ERK1/2 phosphorylation and cyclin D1 expression levels in BRAF-mutated cell lines in comparison to KRAS mutated cells. Upon BRAF inhibition, we also found an increase in p27(Kip1) levels and a more pronounced decrease in the levels of anti-apoptotic protein Bcl-2, specifically in cell lines with BRAF V600E. In conclusion, we have shown that MSI KRAS and BRAF mutant CRC cell lines respond differently to BRAF knockdown. This report provides evidence supporting BRAF as a good target for therapeutic intervention in patients with sporadic MSI CRC harbouring activating mutations in BRAF but not in KRAS.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-3417
pubmed:author
pubmed:copyrightInfo
Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
pubmed:issnType
Print
pubmed:volume
214
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
320-7
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:18098337-Apoptosis, pubmed-meshheading:18098337-Blotting, Western, pubmed-meshheading:18098337-Cell Line, Tumor, pubmed-meshheading:18098337-Cell Proliferation, pubmed-meshheading:18098337-Cell Survival, pubmed-meshheading:18098337-Colorectal Neoplasms, pubmed-meshheading:18098337-Cyclin D1, pubmed-meshheading:18098337-Cyclin-Dependent Kinase Inhibitor p27, pubmed-meshheading:18098337-DNA, pubmed-meshheading:18098337-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:18098337-Genes, ras, pubmed-meshheading:18098337-Humans, pubmed-meshheading:18098337-Microsatellite Instability, pubmed-meshheading:18098337-Mutation, pubmed-meshheading:18098337-Proto-Oncogene Proteins B-raf, pubmed-meshheading:18098337-RNA, Small Interfering, pubmed-meshheading:18098337-RNA Interference, pubmed-meshheading:18098337-Signal Transduction
pubmed:year
2008
pubmed:articleTitle
BRAF provides proliferation and survival signals in MSI colorectal carcinoma cells displaying BRAF(V600E) but not KRAS mutations.
pubmed:affiliation
Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't