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Targeting key proteins of carcinogenesis

Misfolded and disused proteins are eliminated by a cellular shredder called the proteasome. The cell labels the proteins it wants to dispose with Ubiquitin (Ub) in order to avoid the unwanted degradation of still needed proteins. Malfunctions in the ubiquitin-proteasome system can be fatal for the organism. In particular cancer and immunological disorders but also developmental defects are the consequences. The knowledge about the ubiquitination reaction as well as the effect of ubiquitination on diverse cellular functions has already led to the development of highly promising drugs like Bortezomib and Herceptin. The molecular mechanism of Ub conjugation and its biological meaning has been discovered by Avram Hershko, Aaron Ciechanover and Irwin Rose who have been awarded the noble price for their work in 2004. In the current issue of Molecular Cell Prof. Ivan Dikic and his team from the institute of biochemistry II at the University of Frankfurt now describe a novel Ub conjugation reaction that might allow a more efficient manipulation of key proteins in the treatment of cancer and other diseases. Our current view on protein ubiquitination as it is found in the textbooks has to be revised, explains Prof. Mller-Esterl, director of the institute of biochemistry and vice president of the Johann-Wolfgang-Goethe University.

Virtually every process within an eukaryotic cell is directly or indirectly controlled by ubiquitin, says Dikic. This includes fundamental cellular programs such as protein degradation, DNA replication, signal transduction or protein trafficking. Up to now it was believed that the cooperation of three enzymes is needed to attach Ub to another protein: E1, E2 and E3. E1 activates Ub and transfers it to E2, which in turn cooperates with an so-called Ub ligase (E3) that couples Ub to a specific target protein. However, Dikic and colleagues discovered that certain proteins can be ubiquitinated independently of E3 ligases which caused a stir
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Contact: Ivan Dikic
ivan.dikic@biochem2.de
49-696-301-4862
Johann Wolfgang Goethe-Universitt Frankfurt
22-Jun-2007


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