April 09, 2008
During the scientific symposium organized by the Schering Stiftung in Berlin, 60 internationally renowned experts from the USA, Switzerland and Germany met to exchange the latest findings in one of the most important biological systems – the ubiquitin-regulated protein metabolism.
Ubiquitin is a small marker peptide, consisting of 76 amino acids. It is an integral part of all eukaryotic cells. The original Latin meaning of its name is “everywhere” and characterizes its ubiquitous presence in organisms and tissues.
In the 1980s US-scientist Irwin Rose and his Israeli colleagues Avram Hershko and Aaron Ciechanover discovered that targeted protein degradation begins when a ubiquitin chain is attached to target proteins in a multi-step process. A protein marked by ubiquitin is recognized by the protein complex “proteasome” and subsequently cut into smaller subunits – so called peptides. Ubiquitin is released during this process and can re-enter the cellular “protein-recycling-process”. Other important players in the ubiquitin-proteasome-system (UPS) are ATP and the three enzymes E1, E2, and E3. The three scientists Rose, Hershko, and Ciechanover were awarded the Nobel prize for Chemistry in 2004 for the discovery of ubiquitin-mediated protein degradation.
“It was this Nobel prize which brought the attention of many scientists to the huge importance of the ubiquitin-system in cell biology”, says Professor Tony Hunter from Salk Institute for Biological Studies, La Jolla, USA. “During the last 10 years more and more researchers became interested in this subject and the increase in knowledge in this particular field was exponential. Today we know that ubiquitin does a lot more than just regulate protein degradation.” Hunter himself only stumbled upon the ubiquitin system by chance. In 1998 one of his post-doc-students was working on growth factor receptors. He was trying to understand how these receptors were being down-regulated by interaction with ubiquitin ligases. Thus the ubiquitin system became one of the research focuses of Hunter’s group. “I hope that basic research in the field of ubiquitin will help us to identify target proteins for the development of new drugs, especially cancer drugs”, said Hunter at the symposium. “Our research indicates increasingly the close connection between changes in the ubiquitin pathway and various types of cancer. Ubiquitin seems to also play an important role in neurodegenerative processes. For example some neurodegenerative diseases have been shown to accumulate ubiquitin conjugates in afflicted cells. What we are currently looking for, are ways to stop these types of accumulation.” During his opening lecture Professor Hunter pointed out the importance of basic and applied sciences interacting and working together on the way to the development of new pharmaceuticals.
The ubiquitin system is one of the most highly conserved systems throughout eukaryote evolution. It can therefore be studied in simple life forms like yeast or the nematode C. elegans and comparisons to the human organism can be drawn. Such studies can reveal the signaling pathways characteristic for different cell types and diseases. It has been shown that many proteins contain domains that may undergo reversible ubiquitylation and deubiquitylation. This finding motivated scientists from various fields including molecular biology, genetics, and oncology to try and uncover the functions and mechanical connections of the ubiquitin system in cell biology.
At the symposium in Berlin Professor Martin Eilers from the Institute for Molecular Biology and Tumor Research at the Phillips-University in Marburg, Germany presented his latest findings on the Myc oncogene and its regulation by the ubiquitin system. This gene codes for the protein “Myc” which is present in almost all human tumors and plays a key role in cancer. It is an unusual transcription factor which controls the expression of target genes linked to cell reproduction, growth, cell metabolism, and apoptosis – programmed cell death. Eilers observed that poly-ubiquitylation of the Myc-protein not only resulted in degradation by the proteasome, but furthermore led to increased transcriptional activity of the Myc-protein, thus stimulating cell growth. The aim of the work of the Eilers group is to find ways to block signaling pathways that activate Myc-function.
The ubiquitin pathway regulates a great number of different signaling processes in human cells and is important for cell growth, cell differentiation, and the response to cell damage. It is also important in DNA repair processes. Dr. Alan d’Andrea of the Dana Faber Cancer Institute, Boston, Massachusetts, USA, works on a rare human condition called Fanconia Anemia (FA). DNA repair processes in children suffering from FA are dysfunctional. In healthy cells ubiquitylation and deubiquitylation of certain proteins as well as a number of other processes are important for DNA repair. D’Andrea explained in Berlin, “In some patients the pathway is disrupted.” D’Andrea showed that the FANCD2 protein needs to be ubiquitylated for DNA repair to take place. This process is impaired in children with FA who harbour a mutation in the responsible E3-gene. They therefore have higher risks of contracting cancer. They do however respond well to the drug “Cisplatin”, due to the defects in DNA repair mechanisms. D’Andrea transferred these findings to other types of cancer and found 20% of all ovarian cancer tumors, 18% of all breast cancer tumors, 15% of all lung cancer tumors and head and neck squamous cell carcinomas, and 5% of acute myelogenous leukaemia (AML) to contain disruptions of the DNA repair mechanism. This could indicate that patients with these types of tumors would respond to “Cisplatin” as well. “So if a patient has been diagnosed with cancer, we subsequently analyze the DNA repair mechanism. On the basis of this information we can then predict whether a tumor will be Cisplatin sensitive or not”, explains D’Andrea.
A young German scientist at the symposium, Dr. Thorsten Hoppe, from the Centre for Molecular Neurobiology in Hamburg, studies the regulation of polyubiquitylation in the one millimetre long nematode C. elegans. Hoppe and his team observed that ubiquitylation of a molecular chaperone by two specific E3-enzymes is essential for the function of the protein Cdc-48/p97. Together with the p97 protein this chaperone plays an important role in regulating muscle development. Dysfunctional p97 has been found to occur in certain hereditary muscle disorders like inclusion body myopathy (IBM/PFD). Hoppe and his colleagues now hope to advance the search for new diagnostic methods and therapies in this area.
After two and a half days of intensive scientific exchange Dr. Bernard Haendler of the Therapeutic Research Group Oncology of Bayer Schering Pharma AG and co-organizer of the symposium is very pleased. “The Nobel prize in 2004 and the advent of the first proteasome inhibitor on the market acted like a catalyst for ubiquitin research”, says the biochemist. “We now have to look for more specific approaches. This symposium showed how biochemists and geneticists from around the world and involved in both basic and applied research are trying to identify suitable targets within the UPS. This could be relevant for a variety of diseases ranging from cancer and immunodeficiencies to neurodegenerative diseases like Parkinson´s or Alzheimer´s disease. I am convinced that this symposium took us a step further along this path.”
ATP = Adenosintriphosphate
C. elegans = Caenorhabditis elegans
FA = Fanconia Anemia
UPS = ubiquitin-proteasom-system
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