The scientific aspect of the 2004 Nobel Prize in Chemistry won by two researchers from the Technion - a special project of the Science website.
Gilat Simon and Dikla Oren
Molecular kiss of death
By: Gilat Simon
Nobel prize winners in chemistry have revealed the way in which proteins are destroyed inside cells.
Three researchers who revealed the mechanism behind the "molecular kiss of death" - a label that marks proteins destined for destruction - won the Nobel Prize in Chemistry this year.
Irwin Rose from the University of California, along with Aharon Chachanover and Abraham Hershko from the Technion in Israel, studied in the 80s the way in which proteins are broken down inside cells. Their work sparked new ideas about the way cells fire themselves and led to new directions in attempts to treat cancer.
The decision of the Nobel Committee is excellent, says Paolo Di Fiora, a biochemist at the Institute of Molecular Oncology in Milan, Italy. "Their work is original and has a huge future impact, affecting every field of cell biology."
Marked for demolition
In two pioneering papers, which were published in 1980, the trio showed that proteins that are tested for destruction - because they are wrong, for example - are first marked by a molecular label, with a molecule known as ubiquitin ubiquitin. The molecule was first identified in 1975 and is found in many parts of the body - it is so common that its name is derived from this fact - the Latin word for "everywhere" - but the function of the molecule so common was unknown.
Biochemists now know that proteins are marked with several labels of ubiquitin molecules before they are transferred to the proteasome, a barrel blood structure, where the molecules are cut into the building blocks from which they are made and undergo recycling.
The results of this research have spawned countless research projects. Cancer researchers, for example, later learned that ubiquitin modulates the levels of the protein p53, known as "the guardian of the genome" because of its important role in protecting against cancer. Concentrations of p53 increased greatly when a cell suffers DNA damage, thus triggering a chain of actions that stopped cell division while the DNA repair systems worked to repair the damage.
Following on from the initial work that revealed the role of ubiquitin as a molecular label for protein destruction, other researchers have shown that p53 levels rise because ubiquitin stops binding to it, thus preventing it from reaching the proteasome.
This type of work has also inspired pharmaceutical companies, and many of them are now developing drugs that target the ubiquitin system. Inhibition of the proteasome can, for example, prevent the destruction of anti-cancer proteins, a destruction that results from normal recycling processes in the cell. One drug that works in this direction, Velcade, is now approved for use in several types of cancer.
http://www.nature.com/news/2004/041004/full/041004-9.html
The following is the press release of the Nobel Prize Committee, dated 6.10.04:
The Royal Swedish Academy of Sciences has decided to award the 2004 Nobel Prize in Chemistry "for the discovery of ubiquitin-mediated protein degradation" to Aaron Chechenover, Avraham Hershko and Irwin Rose.
Proteins are marked for destruction
Proteins build all living things: plants, animals, including us, humans. In the last decades biochemistry has come a long way towards explaining how the cell produces all its different proteins. However, regarding the breakdown of proteins, there was not much interest in this topic among the scientific community. Aharon Chachanover, Avraham Hershko and Irwin Rose worked against the current and in the early 80s discovered one of the most important cyclical cellular processes - regulation of protein breakdown. For this, they are awarded the Nobel Prize in Chemistry for this year.
Aharon Chachanover, Avraham Hershko and Irwin Rose made us understand that the cell operates as a very efficient testing station, where whey is built and broken down at a very fast pace. The degradation is not carried out randomly, without diagnosis, but through a process that is controlled in detail, so that the proteins that are supposed to undergo degradation at any given moment are molecularly marked, a kind of "kiss of death" if you want to be dramatic... the marked proteins are transferred to proteasomes, those "cellular recycling bins", where they are cut the proteins into small pieces.
The marking is done with a molecule known as ubiquitin. Ubiquitin is attached to a protein destined for degradation, and accompanies it to the proteasome, where it (ubiquitin) is identified, like a key and a lock, and signals that the protein to which it is attached is destined for degradation. Shortly before the protein is compressed into the proteasome, its ubiquitin tag is separated from it and free for reuse, to mark another protein destined for destruction.
Thanks to their work, it is now possible to understand at the molecular level how the cell controls a number of key processes in it by breaking down certain proteins and not others. Examples of processes controlled by ubiquitin-mediated protein degradation are the process of cell division, DNA repair, quality control of newly formed proteins, and important parts of the body's immune defense. When the planned decomposition does not work properly, disease is caused. Cervical cancer and cystic fibrosis are two examples of this. The knowledge and understanding of ubiquitin-mediated protein degradation offers an opportunity to develop drugs against these and other diseases.
Aharon Chechenover Born in 1947 in Haifa, Israel. He received his doctorate in medicine in 1981 from the Technion in Haifa. Chechenover is a professor in the biochemistry department and directs the Research Institute for Medical Sciences named after the Rappaport family at the Technion.
Avraham Hershko Born in 1937 in Karkag, Hungary. He received his Doctor of Medicine degree in 1969 at the Hadassah School of Medicine at the Hebrew University in Jerusalem. Hershko serves as a distinguished professor at the Rapaport Institute for Medical Sciences at the Technion.
Irwin Rose Born in 1926 in New York, United States. He received his doctorate in medicine in 1952 from the University of Chicago in the United States. Specialist in the Departments of Physiology and Biophysics at the University of California College of Medicine in Irvine, United States.
The press release of the Nobel Prize Committee
For a flash animation demonstrating the discovery, click on the following link
Additional, more in-depth information about the discovery and its implications
More information for the general public
