Stability of eukaryotic translation initiation factor 4E mRNA is regulated by HuR, and this activity is dysregulated in cancer.
Eukaryotic translation initiation factor 4E (eIF4E) is encoded by a potent oncogene which is highly elevated in many human cancers. Few studies have investigated how the level, and thus activity, of eIF4E is regulated in healthy (noncancerous) cells and how they become elevated in malignant cells. Here, our studies reveal a novel mechanism by which eIF4E levels are regulated at the level of mRNA stability. Two factors known to modulate transcript stability, HuR and the p42 isoform of AUF1, compete for binding to the 3' untranslated regions (3'UTRs) of eIF4E mRNAs. We identified a distinct AU-rich element in the 3'UTR of eIF4E which is responsible for HuR-mediated binding and stabilization. Our studies show that HuR is upregulated in malignant cancer specimens characterized by high eIF4E levels and that its depletion leads to reduction in eIF4E levels. Further, HuR and eIF4E regulate a common set of transcripts involved in cellular proliferation (cyclin D1 and c-myc) and neoangiogenesis (vascular endothelial growth factor), which suggests a functional connection between HuR and eIF4E in the regulation of these important processes. In summary, we present a novel model for the regulation of eIF4E expression and show that this model is relevant to elevation of eIF4E levels in malignant cells.
Topisirovic
Ivan
I
Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
Siddiqui
Nadeem
N
Orolicki
Slobodanka
S
Skrabanek
Lucy A
LA
Tremblay
Mathieu
M
Hoang
Trang
T
Borden
Katherine L B
KL
D020413:3' Untranslated Regions; D000954:Antigens, Surface / Q000502:physiology*; D001665:Binding Sites; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger; D016601:RNA-Binding Proteins / Q000502:physiology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D039561:Eukaryotic Initiation Factor-4E; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1