BioWorld International Correspondent

LONDON - New insights into the control of an oncogene known to cause leukemia and other tumors in humans could open unexplored avenues of investigation for novel cancer drugs.

A team of researchers based in Germany have shown that a protein called Cyld regulates the oncogene known as Bcl-3.

In the presence of Cyld, Bcl-3 loses marker proteins from its surface that allow it to enter the nucleus. When Cyld is absent, Bcl-3 can enter the nucleus, where it can drive uncontrolled cell division.

The finding, by Professor Reinhard Faessler, of the Max Planck Institute of Biochemistry in Martinsreid, Germany, fits with earlier observations showing that cells in liver, kidney, cervix and colon cancers do not make Cyld.

Faessler said: "Cyld is normally present in all cells of the body. In my opinion, this enzyme is an important tumor suppressor wherever Bcl-3 acts as an oncogene."

The study is published in the May 19, 2006, issue of Cell in a paper titled "Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-kappaB signalling."

Scientists first identified the gene encoding Cyld as the one responsible for a rare disease called familial cylindromatosis. Loss of Cyld causes multiple tumors to develop in hair-follicle cells, particularly in the head region. Later studies suggested that Cyld had a role in inflammation, but how the gene influenced the growth of tumors remained unknown.

Faessler and his team found that mice lacking a functional copy of the gene for Cyld were highly susceptible to chemically induced skin tumors. Mutant mice exposed to tumor-inducing chemicals all developed skin tumors, compared to half of normal mice treated in the same way. The Cyld-deficient mice developed seven times more tumors, which were significantly larger, than the control mice.

Further investigations showed that Cyld-deficient cells responded to the tumor-inducing chemicals by proliferating more rapidly, and that happened because of an accumulation of Bcl-3 in their nuclei.

The researchers went on to carry out a whole series of experiments that teased out the roles of Bcl-3 and Cyld in the cell.

The protein encoded by the Bcl-3 oncogene is a transcription factor: It has the role of initiating and supporting gene transcription. Bcl-3 also works closely with two of the five members of the NF-kappaB family of transcription factors in the nucleus. Those molecules are known to influence many disease processes including inflammation and immune reactions - and, importantly, cell growth.

Two of the NF-kappaB transcription factors, called p50 and p52, have to be activated before the cell can transcribe genes. One way they can become activated is by binding with Bcl-3.

Faessler and his colleagues now have shown that Bcl-3 needs to undergo the process known as ubiquitination in order for the cell to recognize that it needs to enter the nucleus.

And that is where Cyld comes in: It is an enzyme - a deubiquitinase - that removes ubiquitin tags from proteins such as Bcl-3.

Faessler said: "Our results show that Cyld accumulates outside the nucleus. It's a perfect location to prevent Bcl-3's import into the nucleus by binding the protein, removing its ubiquitin tag and hence hindering Bcl-3 translocation into the nucleus."

The team's experiments also showed that, in the absence of Cyld, Bcl-3 accumulates inside the nucleus and, together with p50 or p52, causes cell proliferation.

Faessler added: "Given these results, a universal function as a tumor suppressor for Cyld seems likely in mice and humans."

Additional studies by the group back up this prediction. The team went on to show that, as well as being absent from the benign tumors that develop in people with cylindromatosis, Cyld also is lacking in cells derived from other human skin tumors.

The researchers now are examining the Cyld-deficient mice to find out whether the animals also show an increased prevalence of colon tumors. Early indications suggest that they do, Faessler said.

"We think the Cyld tumor suppressor involved in cylindromas is likely to be important to many other tumors," he concluded. "Since our studies show that Cyld removes an essential type of ubiquitin from Bcl-3, inhibition of Bcl-3's ubiquitination could become a potent anticancer strategy."