Kiss of Death Growth Disorder (Ubiquitin)

Medical Authors and Editors: Barbara K. Hecht, Ph.D. and Frederick Hecht, M.D.

October 7, 2004 -- The 2004 Nobel Prize in Chemistry has been awarded to three scientists who found the "kiss of death" for proteins. Aaron Ciechanover and Avram Hershko of the Technion Israel Institute of Technology in Haifa, Israel and Irwin Rose of the University of California, Irvine shared this year's prize "for the discovery of ubiquitin-mediated protein degradation."

The Kiss of Death

The "kiss of death" for proteins is called ubiquitin. It is itself a protein, a tiny one consisting of only 76 amino acids. It acts as the "kiss of death" for other proteins.

In the normal course of events, proteins need to be broken down and their parts recycled. This is done, it turns out, by tagging proteins with ubiquitin, a process called ubiquination.

Ubiquitin is the signal to the cell's transport machinery to ferry a protein to the proteasome, a barrel-shaped chamber floating in the cell cytoplasm. Proteasomes then slice the protein into bits that are recycled into new proteins.

Antagonizing this process are enzymes that remove ubiquitin from proteins and prevent them being degraded.

Ubiquitin is Ubiquitous

Ubiquitin is appropriately named since it is ubiquitous . It is present in all types of cells.

Ubiquitin is also one of the most highly conserved (least changed) of all proteins during evolution. The sequence of the amino acids that make up ubiquitin is identical in all creatures from fungi and yeast to insects, frogs, and mice to humans. Evolution has not changed ubiquitin one iota.

Inventory Control System

The ubiquitin system is much more than just "waste disposal." Rather, the system acts as an inventory control program. The rapid removal of specific proteins by ubiquitin tells the cell when to turn on or turn off its other functions and when to die. Examples of processes governed by ubiquitin are cell division, DNA repair, the quality control of newly produced proteins, and important parts of the immune defense. When the degradation does not work correctly, we fall ill. Cervical cancer and cystic fibrosis are two examples noted by the Nobel Committee.

An Essential System

So important is the ubiquitin system that about 1,000 of the 35,000 genes in the human genome appear to take part in the ubiquitin system. Ubiquitin is so essential that shortly before the protein is squeezed into the proteasome, its ubiquitin tag is removed for reuse.

Knowledge of ubiquitin offers the opportunity to develop drugs against diseases. In 2003, the US Food and Drug Administration approved a drug called Velcade, which interferes with the workings of the proteasomes as a treatment for multiple myeloma, a cancer of the bone marrow.

International Medical Research

The media announced that this year's Nobel Prize in Chemistry went to one American and two Israelis but in a sense that is misleading. The countries from which they come matters less than the international nature of their work

The American Irwin Rose and Avram Hershko from Israel met at a meeting in 1979. They realized that they were working on the same problem and began a scientific collaboration. Soon Ciechanover, a graduate student of Hershko's, joined the collaboration.

Much of the research that won this Nobel Prize was done during a series of sabbatical leaves that Hershko and Ciechanover took over two decades with Irwin Rose, then at the Fox Chase Cancer Center in Philadelphia.

Medical research transcends national boundaries.


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