Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation

Lior Blau, Revital Knirsh, Iris Ben-Dror, Sivan Oren, Silke Kuphal, Peter Hau, Martin Proescholdt, Anja Katrin Bosserhoff, Lily Vardimon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here,we showthat c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or the half-life of the c-Jun protein but, rather, in the translatability of the transcript. The c-Jun 5′UTR harbors a potent internal ribosomal entry site (IRES) with a virus-like IRES domain that directs cap-independent translation in glioblastoma cells. Accumulation of c-Jun is not dependent on MAPK activity but can be stimulated by a cytoskeleton-dependent pathway. Our findings provide evidence that human c-Jun is an IRES-containing cellular transcript that contributes to cancer development through translational activation. This previously undescribed mechanism of c-Jun regulation might also be relevant to other types of human cancer and offers unique potential targets for therapy.

Original languageEnglish
Pages (from-to)E2875-E2884
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number42
DOIs
StatePublished - 16 Oct 2012

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