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Scientists Hope `Janitors' Lead To Disease Treatments CELL-SIZE AGENTS SWEEP AWAY BODY'S JUNK By Robert S. Boyd Knight Ridder Newspapers Posted on Tue, Oct. 14, 2003 The cells in your body are cluttered with trash -- unneeded or abnormal stuff that can make you sick or even kill you. Fortunately, nature has provided each cell with its own garbage-disposal system to get rid of dangerous junk. A crew of 76 chemical agents acting like tiny janitors prowls the innards of a cell and tag waste materials so other minuscule cleanup workers can find and destroy them. Researchers at many laboratories are discovering new details about this ingenious process, in hopes that their findings will lead to new treatments for cancer, Alzheimer's, Parkinson's and other diseases. ``In the last three years there has been an enormous amount of work to try to understand how this system works,'' said Cecile Pickart, a molecular biologist at Johns Hopkins University in Baltimore. ``It's very exciting when you find new ways of going at disease.'' This waste-disposal apparatus is known as the ubiquitin system because it's ubiquitous, meaning everywhere. An almost identical process is found in most living organisms, from microbes, flies and worms to trees and whales. All these creatures use ubiquitin to mark unwanted substances for elimination, indicating that it's been crucial to life since the beginning. Ubiquitin is a small protein, consisting of 76 amino acids -- chemical compounds made mostly of carbon, hydrogen, nitrogen and oxygen. Proteins, the building blocks of all living organisms, may contain hundreds or thousands of amino acids, linked together in long chains and folded in various complicated ways, like a tangled ball of yarn. A protein is destroyed -- scientists say ``degraded'' -- by unwinding the ball, breaking up the chain and freeing its amino acids to be recycled. Removal process Here's how the process works: First, ubiquitin recognizes the shape of a damaged, badly folded or incorrectly assembled protein. For example, a little piece of a protein may ``become loose and flop around in the breeze,'' Keith Wilkinson, a biochemist at Emory University in Atlanta, said in a telephone interview. ``That's a signal to send it off to be degraded.'' Once it spots a flawed protein, ubiquitin attaches itself to the target, like a forester tagging a tree for removal. Usually several copies of ubiquitin chain themselves together and gang up on the victim. ``Like prisoners, condemned intracellular proteins are shackled with chains to await their fate,'' Wilkinson said. The execution is carried out by a separate complex structure called a proteasome, a hollow cylinder composed of four rings of proteins stacked on top of each other like doughnuts. The cylinder is closed on both ends by protein lids, leaving a cage-like space inside. This space is the death chamber where the doomed protein is broken up. ``Sometimes people liken the proteasome to a blender or a meat grinder,'' Pickart said in a telephone interview. The target protein is ``sucked in like spaghetti,'' she said, and chopped into bits. The process takes from a few minutes to a few hours. When it doesn't work A cell subjected to starvation, radiation, poisoning or infection often contains damaged proteins that must be eliminated. Failure of the ubiquitin system to remove such materials can allow uncontrolled cell growth, the first step toward cancer. Understanding exactly what goes wrong in the ubiquitin-proteasome machinery could help explain why some cells turn cancerous, long before they are detected by conventional methods. Already, drugs that control the proteasome are in clinical trials for the treatment of multiple myeloma, an incurable cancer of the bone marrow, Pickart said. In preliminary tests of one such drug, 70 percent of a group of patients with advanced myeloma saw their conditions stabilize or improve, according to researchers at the Dana-Farber Cancer Institute in Cambridge, Mass. Other functions In recent years, researchers have discovered a number of additional services that ubiquitin performs besides cleanup chores. The system is ``crucial for nearly every significant activity in the cell,'' Marilyn Farquhar, a molecular biologist at the University of California-San Diego, reported in the journal Proceedings of the National Academy of Sciences. IF YOU'RE INTERESTED For more information online, go to http://www.nottingham.ac.uk/biochemcourses/students/ub/ubindex.html Contact Robert S. Boyd at [log in to unmask] SOURCE: The San Jose Mercury News, CA http://www.bayarea.com/mld/mercurynews/living/health/7009488.htm * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn