New Insights into the Control of Cellular Protein Production

Experimental analysis of genetically modified mice revealed that an evolutionary conserved regulatory mechanism of protein production plays an important role in highly developed mammals.

The mouse-model findings of Dr. Klaus Wethmar, Professor Achim Leutz and colleagues could contribute to the development of new therapies and drugs to combat diseases such as cancer. (Genes & Development, doi: 10.1101/gad.557910).*

Proteins are the building blocks of every living cell. The blueprints of the proteins are encoded in the DNA of genes. These blueprints are first transcribed into messenger RNA (mRNA), which then serve as a template for protein production. Some mRNAs contain short upstream open reading frames (uORFs), which control protein production depending on the respective cell physiology. Such regulatory uORFs occur in all organisms from yeast to humans. They are predominantly prevalent in the mRNAs of key regulatory proteins involved in cell proliferation and differentiation as well as cell metabolism and cellular stress management.

In their studies on a mouse model, MDC researchers led by Professor Leutz succeeded for the first time in detecting and measuring the physiological relevance of an uORF conserved in all vertebrates including humans. They discovered that mice deficient in the uORF of an important regulatory protein showed disturbed liver regeneration and impaired bone growth. Based on these findings, together with the widespread prevalence of uORFs in numerous other mRNAs, the MDC researchers suggest that evolutionary conserved uORFs may have comprehensive regulatory functions in the living organism.

The MDC scientists suspect that regulation of protein production by uORFs is associated with many diseases, in particular cancer diseases, since for example the transcripts of growth factors or oncogenes often contain uORFs. “Currently, no drugs exist which specifically target the control of protein production by uORFs,” Professor Leutz explained. “However, since the regulatory function of uORFs is highly relevant, it would be reasonable to screen for drugs which can influence the function of uORFs.”

*C/EBPbeta?uORF mice – a genetic model for uORF-mediated translational control in mammals
Klaus Wethmar1,2, Valérie Bégay1,3, Jeske J. Smink1,3, Katrin Zaragoza1,3, Volker Wiesenthal1,4, Bernd Dörken2, Cornelis F. Calkhoven5 and Achim Leutz1,6,7
1) Max Delbrück Center for Molecular Medicine, Robert Rössle Str. 10, D-13092 Berlin, Germany.
2) Charité, Campus Virchow Klinikum, University Medicine Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
3) These authors contributed equally to this study and are listed in alphabetical order.
4) Current address: Deutsches Zentrum für Luft- und Raumfahrt e.V., Heinrich-Konen-Str. 1, 53227 Bonn, Germany.
5) Leibniz Institute for Age Research – Fritz Lipmann Institute, Beutenbergstr. 11, D-07745 Jena, Germany.
6) Department of Biology, Humboldt-University, Invalidenstr. 43, D-10115 Berlin, Germany.

7) Corresponding author

Barbara Bachtler
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