Clumping proteins disable anti-cancer- network

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Insight in derailing cancer cell offers new clues for cancer treatment

Madelon Maurice en Stefan Rüdiger at the start of their High Potential onderzoek

Scientists at UMC Utrecht and Utrecht University have discovered that genetic changes in the DNA of cancer cells can lead to the formation of small protein aggregates. These aggregates subsequently disable a whole network of tumour-suppressing proteins, thereby causing cancer growth. This new insight in how cancer cells derail may fuel novel strategies for cancer treatment. The results of this study appeared this week in Nature Structural and Molecular Biology. The study was led by cell biologist Dr. Madelon Maurice of UMC Utrecht and biomolecular chemist Dr. Stefan Rüdiger from Utrecht University.

Cancer can be caused by mutations in genes that regulate the generation of new cells. The generation of new cells is carefully stimulated or inhibited by a network of proteins. Until now, it was generally accepted that one of the mutations deactivates the tumour-suppressing Axin protein. However, the scientists in Utrecht have discovered that the mutated Axin protein changes shape and forms small aggregates. “We observed that large protein tentacles stick out of the protein aggregates to trap and switch off a number of other tumour-suppressor proteins”, explains Dr. Stefan Rüdiger, biomolecular chemist at Utrecht University. “So this is how a single gene mutation wipes out the activity of a large group of cell-growth suppressing proteins.”

We expect that our new findings will help obtain more general insights into how aggregates alter cellular behaviour, which will in turn lead to novel research strategies for treatment.

High Potential Grant

In 2006, Madelon Maurice and Stefan Rüdiger received a Utrecht University High Potential Grant to initiate this line of research. The research was also supported by the European Research Council, Netherlands Organisation for Scientific Research, the Medical Research Council of Great Britain, the Boehringer Ingelheim Fonds, the European Union Framework Programme, the Internationale Stichting Alzheimer Onderzoek (ISAO), the European Molecular Biology Organization (EMBO), the Uehara and Kanae Foundations, the Austrian Academy of Sciences, the Bavarian Ministry of Sciences and the German Research Foundation.

Publication

‘Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network’,
Nature Structural and Molecular Biology, doi:10.1038/nsmb.3191.
Researchers from the Bijvoet Center for Biomolecular Research, Utrecht University involved in the project: Tobias Madl, Teck Yew Low, Albert Heck, Rolf Boelens and Stefan Rüdiger.
Researchers from UMC Utrecht: Zeinab Anvarian, Eline van Kappel, Maureen Spit, Ingrid Jordens, Revina van Scherpenzeel, Ineke Kuper and Madelon Maurice.