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Originally published as MBoC in Press, 10.1091/mbc.E08-08-0880 on January 21, 2009

Vol. 20, Issue 6, 1833-1844, March 15, 2009

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RNA Interference Screen Identifies Usp18 as a Regulator of Epidermal Growth Factor Receptor Synthesis

Jason E. Duex, and Alexander Sorkin

Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045

Submitted August 27, 2008; Revised December 19, 2008; Accepted January 12, 2009
Monitoring Editor: Carl-Henrik Heldin

InCytes from MBC

Elevated expression of epidermal growth factor receptor (EGFR) contributes to the progression of many types of cancer. Therefore, we developed a high-throughput screen to identify proteins that regulate the levels of EGFR in squamous cell carcinoma. Knocking down various ubiquitination-related genes with small interfering RNAs led to the identification of several novel genes involved in this process. One of these genes, Usp18, is a member of the ubiquitin-specific protease family. We found that knockdown of Usp18 in several cell lines reduced expression levels of EGFR by 50–80%, whereas the levels of other receptor tyrosine kinases remained unchanged. Overexpression of Usp18 elevated EGFR levels in a manner requiring the catalytic cysteine of Usp18. Analysis of metabolically radiolabeled cells showed that the rate of EGFR protein synthesis was reduced up to fourfold in the absence of Usp18. Interestingly, this dramatic reduction occurred despite no change in the levels of EGFR mRNA. This suggests that depletion of Usp18 inhibited EGFR mRNA translation. In fact, this inhibition required the presence of native 5' and 3' untranslated region sequences on EGFR mRNA. Together, our data provide evidence for the novel mechanism of EGFR regulation at the translational step of receptor synthesis.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-08-0880) on January 21, 2009.

Address correspondence to: Alexander Sorkin (alexander.sorkin{at}ucdenver.edu)

Abbreviations used: DUB, deubiquitination enzyme; EGFR, epidermal growth factor receptor; siRNA, small interfering RNA; UTR, untranslated region; YFP, yellow fluorescent protein.


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