title: Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation.
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 show that 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences,  Tel Aviv University, Tel Aviv 69978,  Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Blau
authors.forename: Revital
authors.initials: R
authors.lastname: Knirsh
authors.forename: Iris
authors.initials: I
authors.lastname: Ben-Dror
authors.forename: Sivan
authors.initials: S
authors.lastname: Oren
authors.forename: Silke
authors.initials: S
authors.lastname: Kuphal
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.forename: Martin
authors.initials: M
authors.lastname: Proescholdt
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
authors.forename: Lily
authors.initials: L
authors.lastname: Vardimon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D014176:Protein Biosynthesis / Q000235:genetics / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012270:Ribosomes / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D008156:Luciferases