Skip to main content

Research Repository

Advanced Search

An internal ribosome entry site in the 5′ untranslated region of epidermal growth factor receptor allows hypoxic expression

Webb, Thomas E.; Hughes, A.; Smalley, D.S.; Spriggs, Keith

An internal ribosome entry site in the 5′ untranslated region of epidermal growth factor receptor allows hypoxic expression Thumbnail


Authors

Thomas E. Webb

A. Hughes

D.S. Smalley



Abstract

The expression of epidermal growth factor receptor (EGFR/ERBB1/HER1) is implicated in the progress of numerous cancers, a feature that has been exploited in the development of EGFR antibodies and EGFR tyrosine kinase inhibitors as anti-cancer drugs. However, EGFR also has important normal cellular functions, leading to serious side effects when EGFR is inhibited. One damaging characteristic of many oncogenes is the ability to be expressed in the hypoxic conditions associated with the tumour interior. It has previously been demonstrated that expression of EGFR is maintained in hypoxic conditions via an unknown mechanism of translational control, despite global translation rates generally being attenuated under hypoxic conditions. In this report, we demonstrate that the human EGFR 5′ untranslated region (UTR) sequence can initiate the expression of a downstream open reading frame via an internal ribosome entry site (IRES). We show that this effect is not due to either cryptic promoter activity or splicing events. We have investigated the requirement of the EGFR IRES for eukaryotic initiation factor 4A (eIF4A), which is an RNA helicase responsible for processing RNA secondary structure as part of translation initiation. Treatment with hippuristanol (a potent inhibitor of eIF4A) caused a decrease in EGFR 5′ UTR-driven reporter activity and also a reduction in EGFR protein level. Importantly, we show that expression of a reporter gene under the control of the EGFR IRES is maintained under hypoxic conditions despite a fall in global translation rates.

Citation

Webb, T. E., Hughes, A., Smalley, D., & Spriggs, K. (in press). An internal ribosome entry site in the 5′ untranslated region of epidermal growth factor receptor allows hypoxic expression. Oncogenesis, 4, Article e134. https://doi.org/10.1038/oncsis.2014.43

Journal Article Type Article
Acceptance Date Oct 15, 2014
Online Publication Date Jan 26, 2015
Deposit Date May 16, 2017
Publicly Available Date May 16, 2017
Journal Oncogenesis
Electronic ISSN 2157-9024
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 4
Article Number e134
DOI https://doi.org/10.1038/oncsis.2014.43
Public URL https://nottingham-repository.worktribe.com/output/742647
Publisher URL https://www.nature.com/oncsis/journal/v4/n1/full/oncsis201443a.html
Contract Date May 16, 2017

Files





You might also like



Downloadable Citations