Published online 6 October 2004 | Nature | doi:10.1038/news041004-9


Molecular kiss of death

Chemistry Nobel winners unmasked how proteins are destroyed in cells.

Avram Hershko takes a third of the prize.Avram Hershko takes a third of the prize.© Israel Institute of Technology.

Three researchers who unravelled the mechanism behind a molecular kiss of death - a tag that marks proteins for destruction - have been awarded this year's Nobel Prize in Chemistry.

Irwin Rose of the University of California, Irvine, together with Aaron Ciechanover and Avram Hershko from the Israel Institute of Technology in Haifa, transformed cell biology during the early 1980s through their studies of how proteins are broken down inside cells. Their work sparked new ideas about how cells regulate themselves and new directions in attempts to treat cancer.

The decision is "wonderful", says Paolo Di Fiore, a biochemist at the FIRC Institute of Molecular Oncology in Milan, Italy. "Their work is seminal," he adds. "It affects every aspect of cell biology."

Tagged for destruction

In two pioneering papers1,2 published in 1980, the trio showed that proteins selected for destruction - because they are faulty, for example - are first tagged with a molecule known as ubiquitin. The molecule had been identified in 1975 and is found in many different parts of the body - hence its name, taken from the Latin for 'everywhere' - but its function was not understood.

Biochemists now know that proteins are tagged with several ubiquitin molecules before being shuttled to the proteasome, a barrel-shaped structure that chops up and recycles molecules.

The results spawned numerous new research projects. Cancer researchers, for example, subsequently learned that ubiquitin regulates the levels of the protein p53, dubbed the 'guardian of the genome' for its role in protecting against cancer. Concentrations of p53 shoot up when a cell suffers DNA damage, triggering a halt in cell division while DNA repair systems get to work.

Following the work of Rose and colleagues, researchers showed that p53 levels rise because the ubiquitin stops binding to it, preventing it from reaching the proteasome.

Such work also inspired drug companies, and many are now working on drugs that target the ubiquitin system. Inhibiting the proteasome can, for example, prevent anticancer proteins from being destroyed by the cell's normal recycling process. One drug that acts in this way - Velcade, marketed by Millennium of Cambridge, Massachusetts - is now approved for the treatment of certain cancers.

As with any Nobel prize, questions are likely to be asked about the panel's decision. One researcher who may feel hard done by is Alexander Varshavsky of the California Institute of Technology in Pasadena.

Varshavsky also made important contributions to our understanding of protein degradation. In 2000, he shared the prestigious Albert Lasker Award for Basic Medical Research with Ciechanover and Hershko. Why Rose and not Varshavsky got the nod from the Nobel committee is unlikely to be revealed, however, as the panel have a policy of not discussing such decisions. 

  • References

    1. Ciechanover A., et al. Proc. Natl Acad. Sci. USA, 77. 1365 - 1368 (1980). | Article | PubMed | ChemPort |
    2. Hershko A., et al. Proc. Natl Acad. Sci. USA, 77. 1783 - 1786 (1980). | Article | PubMed | ChemPort |