INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma.

Details

Serval ID
serval:BIB_35676B95BC1E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma.
Journal
Oncogene
Author(s)
Lachat Y., Diserens A.C., Nozaki M., Kobayashi H., Hamou M.F., Godard S., De Tribolet N., Hegi M.E.
ISSN
0950-9232 (Print)
ISSN-L
0950-9232
Publication state
Published
Issued date
2004
Peer-reviewed
Oui
Volume
23
Number
41
Pages
6854-6863
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, DeltaEGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16(INK4a)/p19(Arf) or p53, respectively, with or without ectopic expression of DeltaEGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of DeltaEGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/DeltaEGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/DeltaEGFR(2-7) in glioblastoma patients.
Keywords
Animals, Astrocytes/enzymology, Cyclin-Dependent Kinase Inhibitor p16/physiology, Enzyme Activation, Glioma/enzymology, Mice, Mitogen-Activated Protein Kinases/metabolism, Phosphorylation, Quinazolines, Receptor, Epidermal Growth Factor/antagonists & inhibitors, Tyrphostins/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 13:06
Last modification date
20/08/2019 13:22
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