Linked Life Data

17486080

Source:http://linkedlifedata.com/resource/pubmed/id/17486080

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2007-10-4
pubmed:abstractText
Clear cell renal cell cancer (CC-RCC) is a highly chemoresistant tumor characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene. The prognosis is reportedly worse in patients whose tumors express immunoreactive type I insulin-like growth factor receptor (IGF1R), a key mediator of tumor cell survival. We aimed to investigate how IGF1R expression is regulated, and found that IGF1R protein levels were unaffected by hypoxia, but were higher in CC-RCC cells harboring mutant inactive VHL than in isogenic cells expressing wild-type (WT) VHL. IGF1R mRNA and promoter activities were significantly lower in CC-RCC cells expressing WT VHL, consistent with a transcriptional effect. In Sp1-null Drosophila Schneider cells, IGF1R promoter activity was dependent on exogenous Sp1, and was suppressed by full-length VHL protein (pVHL) but only partially by truncated VHL lacking the Sp1-binding motif. pVHL also reduced the stability of IGF1R mRNA via sequestration of HuR protein. Finally, IGF1R mRNA levels were significantly higher in CC-RCC biopsies than benign kidney, confirming the clinical relevance of these findings. Thus, we have identified a new hypoxia-independent role for VHL in suppressing IGF1R transcription and mRNA stability. VHL inactivation leads to IGF1R upregulation, contributing to renal tumorigenesis and potentially also to chemoresistance.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6499-508
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma.
pubmed:affiliation
Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, and Department of Urology, Churchill Hospital, Oxford, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't