30 May 2006

NF Kappa B Update: Interactions with Oncogene and Tumour Suppressor

Several weeks ago, I discussed the NF Kappa B family of transcription factors as possible targets for cancer therapies. Now researchers at two German research institutes have uncovered further details into how NF Kappa B interacts with an important leukaemia oncogene, and how transcription of the oncogene is blocked by a tumour suppressor protein by way of de-ubiquitisation (be patient, this is important).

During the process of genetic transcription, Bcl-3(oncogene product [transcription factor]) cooperates with other, unusually important transcription factors which belong to the NF-KB-family. Its five members influence a broad spectrum of disease processes, like infections and immune reactions, as well as cell growth. Two representatives of this group, p50 and p52, must themselves first be activated in order to initiate the transcription. One important mechanism for doing that is Bcl-3 binding. Until now, we have known that Bcl-3 can cooperate with p50 or p52, causing intense cell growth and ultimately cancer. For such cooperation, however, Bcl-3 has to first enter the nucleus, where DNA and the NF-KB proteins can be found. The team from Munich, led by 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 activity of Cyld functions as a tumour suppressor in all tumours in which the Bcl-3 oncogene plays a role."

This is just a small picture view of what is going on with one particular oncogene and a likely tumour suppressor that tries to block its expression. The fact that it involves the NF Kappa B family as co-transcription factors is something to be filed away for future use. NF Kappa B sits at the center of many cell processes, and will probably be targeted at some point in the cell signalling pathway, probably more than one point--since finding the precise target point in a complex pathway for specific disease processes can be a trial and error procedure.


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