SCIENTISTS have discovered how a rogue protein molecule causes several types of human cancer – publishing their report in the prestigious journal Cell today* (Thursday).

The team, funded by Cancer Research UK, The Institute of Cancer Research and The Wellcome Trust, analysed the structure of a protein called B-RAF – which is altered in a large proportion of malignant melanomas, bowel, thyroid and ovarian cancers.

They found that when B-RAF is faulty it radically rearranges its shape, triggering a chain of events that lead to cancer. Researchers believe their findings will help accelerate the search for potent and specific drugs that can target the protein and stop the growth and spread of these cancers.

Genes carry the coded information needed to assemble specific protein molecules. In 2002, researchers on this study formed part of the team which discovered that faults in the B-RAF gene could lead to cancer.

Scientists now know the B-RAF protein controls the growth and division of healthy cells during development. They believe that in certain cancers the gene is damaged and so the protein is permanently switched on allowing cells to multiply out of control. But how damage to the B-RAF protein kick-starts cell division has remained a mystery until now.

Co-author Dr Richard Marais, from the Cancer Research UK Centre for Cell and Molecular Biology at The Institute of Cancer Research, says: "Studies have now identified over 30 different faults in B-RAF that cause cancer. As well as contributing to the majority of melanomas the gene is also involved in the development of a large proportion of bowel, thyroid and ovarian cancers.

"We estimate that approximately 5,000 people die in the UK each year from cancers that have BRAF mutations."

In this study researchers analysed 22 different mutations in the B-RAF gene that occur in cancer. They looked at the effect of each mutation on the activity and structure of B-RAF.

They combined studies that measured activity with a sophisticated technique called X-ray crystallography to generate a precise 3-D image of the protein. The technique scans a crystal of the molecules with X-rays, which are reflected by the protein, revealing its shape.

They found that damage to the gene caused the B-RAF protein to alter its shape – flipping from a dormant state to an active one. The active B-RAF is then able to kick start cell growth and division by signalling to a molecule called MEK, which is part of a cascade of controls that govern the process.

Co-author Professor David Barford, from the Section of Structural Biology at The Institute of Cancer Research, says: "Most of the mutations we looked at occur in the two regions of the gene that are crucial to holding B-RAF in its inactive form. When either of these regions is damaged B-RAF is able to rearrange its shape. This change activates the protein and plays a key role in driving the uncontrolled cell proliferation and survival that leads to cancer."

Dr Marais adds: "Now we know how B-RAF is activated in cancer we can develop specific and potent drugs that can lock its structure back into its inactive form."

The team is now screening tens of thousands of compounds to find those that can block the activity of B-RAF in cancer cells.

Professor Peter Rigby, Chief Executive of The Institute of Cancer Research, comments: "This latest research is a major step forward in our understanding of the way in which B-RAF works and brings us a step closer to developing drugs which can directly target the faulty protein."

Dr Lesley Walker, Director of Information at Cancer Research UK, says: "B-RAF is important in the development of a number of cancers. Now we have a clearer picture of its shape and function we can exploit this knowledge to guide the design of novel therapeutics."

*Cell Vol. 116, No. 6

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Notes for editors

B-RAF belongs to a family of proteins whose other members are called A-RAF and C-RAF. These proteins are involved in controlling the growth, division and survival of cells.

Cancer Research UK is the Europe's leading charity dedicated to research on the causes, treatment and prevention of cancer. We fund over 3000 scientists, doctors and nurses based throughout the UK.

The Institute of Cancer Research is a centre of excellence with leading scientists working on cutting edge research. It was founded in 1909 to carry out research into the causes of cancer and to develop new strategies for its prevention, diagnosis, treatment and care.

The Wellcome Trust is an independent research-funding charity established in 1936 under the will of tropical medicine pioneer Sir Henry Wellcome. The Trust's mission is to promote research with the aim of improving human and animal health and it currently spends more than £400m p.a.

The Technology Transfer Division manages the charity's intellectual property portfolio and related matters and also provides "greenhouse" translation funding for early-stage healthcare technology development. Over 30 research and license agreements have been transacted and the Division has an interest in over 20 life science SME's located in the UK or US.
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