A tumour suppressor in mice and men

Prof. Reinhard Fässler, showed that the transcription factor is helped by a molecular "ticket".

Large numbers of ubiquitin molecules can be attached in sequence to proteins. A certain kind of binding marks this protein as "rubbish" which has to be removed. Another type of ubiquitin attachment to proteins functions as a kind of transport signal. It negotiates the transfer, for example, of proteins into the nucleus. The study shows that this is the case with Bcl-3. It only functions like this, however, when Cyld does not get in the way. This protein was first found in patients suffering from cylindromas. These are tumours that grow on the face, neck, and scalp. Cyld is a deubiquitinase - an enzyme that removes ubiquitin groups from other proteins. "We could show in our study that Cyld proteins can accumulate around the nucleus," says Fässler. "They can intercept Bcl-3 there and prevent it from being imported into the nucleus, by removing ubiquitin appendages." This is the first evidence ever of a specific mechanism that regulates and controls the Bcl-3 oncogene.

The team of researchers from Munich flawlessly reconstructed Cyld interaction with Bcl-3. They demonstrated every step in the process, from the recruiting of Cyld over to the nuclear membrane, to the ubiquitinisation of Bcl-3, and Cyld's reversal of this process. They also showed in detail that Bcl-3 collects without Cyld in the nucleus, and can cause cell proliferation with p50 and p52. All in all, it seems not unlikely that Cyld functions as a tumour suppressor in mice and in humans. In humans, there is evidence that a defective Cyld gene can have negative consequences, like the largely benign tumours of cylindromas. The researchers also found very little, or no, Cyld in the cells of other skin tumours. The situation is similar in some cases of liver, kidney, and uterine cancer. "Cyld is expressed in every cell in the body", Fässler says. "I believe personally that the deubiquitinase activit

Contact: Eva-Maria Diehl

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