By LESLIE H. LANG UNC-CH School of Medicine
CHAPEL HILL, N.C. - Scientists at the University of North Carolina at Chapel Hill have discovered three genes crucial to the survival of cells. The genes select cellular proteins for the disposal and eventual recycling of their components.
Because some of these proteins have been implicated in cancer and other human illnesses, failure or disruption of this cellular mechanism may promote the disease process, according to Dr. Yue Xiong, assistant professor of biochemistry and biophysics at the UNC-CH School of Medicine.
"Balance is the key word. How the cell cycle of growth and division maintains balance is what we're studying," Xiong says. "It may be that human diseases are somehow linked to a degradation breakdown, one that leads to imbalance of proteins."
Xiong, a member of the UNC Lineberger Comprehensive Cancer Center, points to the known tumor suppressor p53 as an example. Normally, p53 is present within cells in relatively minute amounts. "If it's degraded too much, the protein never accumulates and you get tumor development. If this protein accumulates too much, the cell won't grow," he explains.
Another example is the cancer-related myc (pronounced MIK) oncogene and the protein it transcribes. "If this protein accumulates too much, you get cancer because this is the gene driving cells to grow, grow and grow."
A third example is proto-oncogene, cyclin D, which was discovered several years ago by Xiong and his colleagues at the Cold Spring Harbor Laboratory in New York Cyclin D, together with its partner, CDK4, controls a critical cellular decision: to divide and grow or to arrest. Cyclin D has been found in a high percentage of human head and neck cancers and breast cancers. "When over-expressed in mouse mammary glands, cyclin D causes breast cancer," Xiong says.
The UNC-CH discovery is the first to clarify a key component of the cellular degradation process or pathway - specifically, the mechanism by which proteins within cells are selected and "marked" for removal and destruction after they have done their job.
In their report published in the April 23 issue of the journal Molecular Cell, Xiong and his co-authors, Tomohiko Ohta, Jennifer J. Michel and Arndt J. Schottelius, describe having identified the proteins ROC1, ROC2 and APC11. These closely related proteins, particularly ROC1, combine with other proteins called cullins to form an enzyme, a ubiquitin ligase. This enzyme then accelerates a biochemical reaction in which a molecule called ubiquitin is attached to cellular proteins. Thus "ubiquitinized," the protein is marked for disposal and degradation. After degradation, the cell then recycles the protein's amino acids to build other proteins.
"Once a protein is attached to ubiquitin, another cellular mechanism recognizes that it's ubiquitinated and takes it to a specific place called the proteasome," Xiong points out. "It's like garbage collection. Unless you put your garbage out in the street, it won't get picked up and taken to the dump." In cells, the dumpsite is the proteasome's protein degradation machinery.
"Abnormal level of proteins, too high in the case of oncoproteins such as myc or cyclin D or too low in the case of tumor suppressor proteins such as p53, have one common consequence. They drive cells to continue proliferating when normal cells would not," Xiong says. "How these proteins in tumor cells escape from normal ubiquitin-mediated degradation is currently unknown."
Xiong and scientists elsewhere are working to solve this problem by identifying essential components involved in the normal control of protein degradation.
In their journal report, the UNC-CH researchers also note that the newly identified proteins can combine with five different cullins. "That means there are many binary ubiquitin ligases," Xiong says. "And it raises the possibility that degradation of different proteins may each require a different ubiquitin ligase."
Finally, in a demonstration of ROC1's importance to cell survival, the research team removed the gene from yeast cells, and the cell then died. "So in yeast, if you remove ROC1, the cell dies because it lost its ability to biochemically label a number of substrate proteins with ubiquitin. If this doesn't take place, proteins accumulate and kill the cells," Xiong says.
And when the researchers inserted human ROC1 (or ROC2) into yeast cells devoid of their only ROC gene, the cells were rescued from death. "This tells you how conserved the gene is, how functionally important it really is," Xiong says.
Xiong is this year's recipient of the American Association of Cancer Research's Gertrude B. Elion Award, which is presented annually to non-tenured scientists engaged in cancer causative, preventive, and/or treatment research.
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