Diverse age-related diseases -- including cancer, atherosclerosis, arthritis and Alzheimer's disease -- may have a common genetic link, researchers at the University of Illinois at Chicago have found.
The finding suggests that one day it may be possible to prevent or combat all these diseases with drugs that target this common link.
In the April 11 issue of the Proceedings of the National Academy of Sciences, the scientists report that the activation of a single gene known as p21 may contribute to the development of a multitude of diseases of old age.
The p21 gene serves as a brake that stops cells from growing when they are damaged by toxins or radiation, thus giving them time for repair. During normal aging, the p21 gene also stops cells from dividing as the cells grow senescent.
Using recombinant DNA methods, the UIC researchers turned on the p21 gene in human cells grown in the laboratory. They then used the powerful tools of modern genomics, together with information on the sequence of the human genome, to study the effects of p21 on thousands of other genes.
"The pattern was striking," said Igor Roninson, the senior author of the study and professor in the department of molecular genetics in UIC's College of Medicine. "Turning on this one gene brought about changes in numerous other genes that have already been implicated in aging and age-related diseases."
When the p21 gene was turned on, the cells took on the characteristics of aging cells: they stopped growing, became flat and granular in appearance and started making enzymes typically produced by senescent cells.
To understand these effects at the molecular level, research assistant professor Bey-Dih Chang and other scientists in Roninson's laboratory analyzed the activity of multiple other genes in response to p21's stimulation.
The researchers found that p21 selectively inhibited more than 40 genes known to be involved in DNA replication and cell division, thus immediately arresting cell growth.
At the same time, p21 increased the activity of about 50 other genes. Unexpectedly, the researchers said, about 20 of these turned out to be genes manufacturing proteins secreted by the cell into its environment. Some of these proteins, made by cells rendered senescent by p21, either inhibit the death or stimulate the growth of neighboring cells. According to Roninson, this paradoxical growth-stimulating activity of growth-arrested cells resembles the functions of certain cells found in human cancers, suggesting that p21 may be involved in promoting the development of tumors.
Other genes stimulated by p21 produce proteins that cause or are associated with several age-related diseases. These proteins include the precursor of the beta-amyloid peptide, the main component of plaques found in the brains of Alzheimer's patients. These plaques form after beta-amyloid is modified by an enzyme called transglutaminase, which Roninson and his colleagues found was also stimulated by p21. Other p21-activated genes produce various proteins and enzymes that contribute to atherosclerosis, arthritis and amyloidosis.
Research is now under way to confirm that p21 acts similarly in other human tissues and to develop a drug that would prevent the induction of disease-promoting genes by p21.
Other authors of the study are UIC researchers Keiko Watanabe, Eugenia Broude, Jing Fang, Jason Poole and Tatiana Kalinichenko.
The research was supported by the National Cancer Institute and the National Institute for Dental and Craniofacial Research. For copies of the paper, call the National Academy of Sciences at 202-334-2138.
UIC's College of Medicine is the nation's largest medical school. One out of six Illinois doctors is a graduate of the college, as are 70 percent of the minority physicians practicing in Chicago. The college produces more medical school faculty than all but five schools in the country.
With 25,000 students, the University of Illinois at Chicago is the largest and most diverse university in the Chicago area and one of only 88 national Research I universities. Located just west of Chicago's Loop, UIC is a vital part of the educational, technological and cultural fabric of the entire metropolitan region.
Journal
Proceedings of the National Academy of Sciences