Tightly Controlled Protein Destruction Drives The Cell Cycle

September 18, 1998

Ubiquitin -- as the name suggests -- is found in cells throughout the body. In fact, this 76-amino-acid-long protein appears in nearly identical form in many other species, even some quite distant from humans on the phylogenic tree. Yeast ubiquitin, for example, differs from the human protein by only three of its amino-acid building blocks. What, then, makes ubiquitin so vital that it has been so strongly conserved during evolution? Research from the laboratory of Sandra L. Holloway, PhD, an assistant professor of genetics at Penn and assistant investigator with the Howard Hughes Medical Institute, is beginning to answer that question.

Holloway's studies have shown that ubiquitin plays a crucial role in precisely coordinating the transition between two steps in mitosis, a step in the cycle of cell division that underlies all growth, renewal, and repair.

After the cell has duplicated the DNA in its chromosomes in the metaphase step of mitosis, but before the chromosomes have separated in the anaphase step, a group of 13 proteins known as the anaphase-promoting complex, or APC, identifies and tags pivotal metaphase proteins with ubiquitin.

Then, in a process referred to as ubiquitin-mediated proteolysis, a large tubular enzyme called a proteosome recognizes the protein-ubiquitin pairing and destroys the protein while releasing the ubiquitin to be used again. The destruction of the metaphase proteins frees the cell to continue to the anaphase step in the cell cycle.

Currently, experiments in Holloway's laboratory are aimed at understanding precisely which APC proteins see and bind to specific proteins to facilitate the metaphase-anaphase transition. Her team recently discovered that an APC component called CDC23 binds to cyclin, a protein known to be essential in earlier steps of mitosis, leading to its destruction. According to Holloway, disruptions in the ubiquitin system have been linked to a number of human diseases, including colorectal and other cancers, Parkinson's disease, Alzheimer's disease, cystic fibrosis, Down's syndrome, and less common disorders such as Liddle's syndrome and Angelman syndrome. A better understanding of ubiquitin-mediated proteolysis, therefore, could form the basis for the development of new drugs to treat these and other diseases.
The University of Pennsylvania Medical Center's sponsored research ranks third in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1997, the medical center received $175 million. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's website http://www.med.upenn.edu; EurekAlert! http://www.eurekalert.org, a resource sponsored by the American Association for the Advancement of Science; and Newswise http://www.newswise.com.

University of Pennsylvania School of Medicine

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