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please contact:

Carol Cheneval
Coordination Symposium
T: +41 22 704 36 31
F: +41 22 704 36 37
cheneval@jeantet.ch





Louis-Jeantet
Foundation (LJF)

Chemin Rieu 17
P.O. Box 270
1211 Geneva 17
Switzerland
T: +41 22 704 36 36
F: +41 22 704 36 37
info@jeantet.ch


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Stephen Lee

Department of Cellular and Molecular Medicine, Department of Medicine, University of Ottawa, Ontario, Canada

Wednesday, October 23, 09:25 – 09:50

The role of RNA Hypoxia Response Element (rHRE)-driven Protein Synthesis in the Hypoxic Cell Phenotype

Protein synthesis is typically initiated by the binding of the eukaryotic initiation factor 4E (eIF4E) to the 5’ cap found on the vast majority of mRNAs. Hypoxia is a potent inhibitor of eIF4E-directed translation raising an intriguing question as to how hypoxic cells are able to synthesize proteins. We recently reported that hypoxic cells exploit an alternative cap-dependent translation machinery to synthesize the vast majority of their proteins. This system relies on the participation of several new components to the cellular translation apparatus, including the oxygen-regulated HIF2α, the RNA-binding protein RBM4 and eIF4E2, an homolog of eIF4E that escapes hypoxic inhibition. The HIF2a/RBM4/eIF4E2 complex is recruited by a small RNA motif present on the 3’UTR of mRNAs, referred to as the RNA Hypoxia Response Element (rHRE). We will show that rHRE-mRNAs undergo translation exclusively during hypoxia to synthesize more than 90% of the hypoxic cell proteome. In contrast, mRNAs that do not encode an rHRE are efficiently translated in normoxic, but not in hypoxic, conditions. As such, preventing rHRE-mediated protein synthesis abolishes the ability of cancer cells to form a hypoxic tumor core, and thus a cellular mass of more than ½ mm, as they are unable to synthesize proteins in the absence of oxygen. A model will be presented whereby cells switch to rHRE-directed translation to confer the hypoxic cell phenotype.

Biography

Stephen Lee received his Ph. D from McGill University in 1994 before joining as a postdoctoral fellow the laboratory of Dr. Richard Klausner, the former Director of the (US) National Cancer Institute. He was recruited by the University of Ottawa in 1998, received the Harold E. Johns Award from the National Cancer Institute of Canada in 2004 and was promoted to the rank of Full Professor in 2008. The laboratory of Dr. Lee is funded by grants from Canadian Institutes of Health Research and focuses on the role of non-coding RNA and protein synthesis in the cellular adaptation to hypoxia.

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