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Molecular gate-keeper holds cancer at bay

Newly discovered cell mechanism protects from tumor growth

Munich, 05/22/2006

 The activity of so-called oncogenes can lead to tumors and cancer. One of them, Bcl-3, lies at the root of leukemia in humans and other diseases. Professor Alexander Pfeifer and Katharina Hennecke at the Ludwig-Maximilians-Universität (LMU) Munich together with researchers at the Max-Planck-Institute of Biochemistry at Martinsried, a high-tech hub on the outskirts of Munich, have discovered a new mechanism that regulates this important oncogene, as reported in Cell. They found that a protein called Cyld can control Bcl-3 and protect mice from malignant growth. If Cyld fails, a cellular signaling pathway leads to aberrant proliferation of the cell. Cyld could be one of the Bcl-3 oncogene’s most important antagonists – not only in mice but also in men.

Growth, division and differentiation of cells are among the best controlled processes in the body. That is, because even one single cell “out of control” can cause a malignant tumor. Healthy cells control oncogenes through the activity of tumor suppressor genes. But until now Bcl-3’s specific antagonists were unknown. As a transcription factor, Bcl-3 can only function in the nucleus. There it works closely with members of an important family of transcription factors called “NF-κB” to initiate and support the activation of genes. NF-κB proteins influence a broad spectrum of pathogenic processes like inflammation, immune reactions – and, most importantly, cell growth. Two of these transcription factors, p50 and p52, have to be activated first to transcribe genes. Binding with Bcl-3 is one way for them to achieve this. It is well established that when Bcl-3 teams up with p50 or p52 it can cause cell proliferation and even cancer. However, it was not known how Bcl-3’s entry into the nucleus is regulated. The Munich team has now identified the ticket for this trip into the nucleus: Ubiquitin.

Ubiquitin is a protein tag that marks proteins for different fates. One way of attaching this tag makes it a signal for import into the nucleus, which is what happens to Bcl-3. That is, unless Cyld gets in the way. This protein is a deubiquitinase, an enzyme which removes ubiquitin tags from proteins. The new results show that Cyld accumulates outside the nucleus if needed. There it can prevent Bcl-3’s import into the nucleus by binding the protein and removing its ubiquitin. This is the first proven mechanism to control and regulate the important Bcl-3-oncogene. The Munich team managed to reconstruct the interaction between Cyld and Bcl-3 from Cyld’s accumulation at the nuclear membrane to Bcl-3’s ubiquitination and the removal of the tag.

Equally impressive and detailed is the study of Bcl-3’s activity without Cyld. The protein accumulates inside the nucleus and together with p50 or p52 causes cell proliferation. Given these results, it seems likely that Cyld has a universal function as a tumor suppressor for Cyld in mice and humans. This inference for humans has been suggested by findings that Cyld has been missing or lacking in different tumors of the skin, liver, kidney, uterine cervix and colon. Cyld is present in all cells of the body. It’s tempting to speculate that it serves as an important tumor suppressor wherever Bcl-3 acts as an oncogene.

Publication:
Ramin Massoumi, Katarzyna Chmielarska, Katharina Hennecke, Alexander Pfeifer, and Reinhard Fässler
Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF- κB Signaling
Cell, May 19, 2006

Contact:
Professor Dr. Alexander Pfeifer
Ludwig-Maximilians-Universität (LMU) Munich
Tel.: +49 89 2180 77654
Fax: +49 89 2180 77326
Email: alexander.pfeifer@cup.uni-muenchen.de
Web: www.cup.uni-muenchen.de/ph/aks/biel/labmembers/pfeifer.html

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