May 4, 1999 Scientists at the University of California San Francisco have discovered a transcription factor that regulates part of the cycle that makes new copies of the cells in the human body. As more specifics are identified about the role of this and related cell cycle regulators, the knowledge may lead to new ways to stimulate repair of heart muscle cells after damage caused by a heart attack or birth defects.
Harold S. Bernstein, MD, PhD, assistant professor of pediatrics and investigator at the UCSF Cardiovascular Research Institute, reported on his research group's discoveries about human Cdc5 (hCdc5) on May 2 at the Pediatric Academic Societies' 1999 annual meeting in San Francisco.
The research, supported in part by the March of Dimes, is in its early stages. "The reason we are so interested in the cell cycle is that we need better treatments for children whose heart muscle is damaged due to heart abnormalities -- the most common form of birth defect." Bernstein said. If the work leads to a way to stimulate heart muscle repair, it also could help the 900,000 American adults struck with a heart attack each year. And because hCdc5 appears to regulate a crucial point in the cycle when cell duplication either halts or continues, knowledge about its actions could uncover potential new targets for drugs to stop the uncontrolled cell division in cancer.
Using recombinant DNA techniques, Bernstein cloned hCdc5 in 1997 and showed that it is a novel human protein involved in the division of human cells. Since then, he and his research team have shown that it binds to DNA and acts as a transcription factor -- it regulates genes that instruct a cell to start the final phase of cell division. Bernstein and the University of California have obtained a patent protecting the use of hCdc5 for therapeutic approaches to cancer and muscle disease.
In their presentation to the Society for Pediatric Research, Bernstein's team reports on work to identify specific sites on the human genome where the transcription factor may bind. "Once we identify the genes that hCdc5 and similar transcription factors regulate, a new group of targets for controlling cancer and for regeneration of myocardial (heart) cells may be revealed," Bernstein said.
As a pediatric cardiologist, Bernstein is interested in cell division because heart cells normally do not divide. In fetal life, the heart takes shape and grows by adding more cells, but within weeks after birth every myocardial cell has stopped dividing. Every cell contracts with each heart beat, 60-120 times a minute -- by Bernstein's estimate, about 4 billion beats in a lifetime. But like the brain, the heart's cells do not divide and thus cannot repair damaged tissue after an injury.
In many other mammalian organs, cells replenish themselves and repair damage by re-entering the cell cycle. In this cycle, the cell stays for some time in a phase called G1 as it prepares to duplicate its content of DNA. Next it enters a phase called S for synthesis, when the DNA in its nucleus is replicated and the copied DNA is checked for mistakes. In a third phase, G2, further checking goes on and repairs are made. Finally, assuming the cell passes its own internal quality control mechanisms, the M phase -- mitosis -- divides the DNA equally between two daughter cells.
Some cells, such as skin or blood cells, undergo this cycle regularly. Others, such as muscle cells, can be stimulated to shift from normal, specific functioning into cell replication as needed for damage repair.
Myocardial cells remain permanently in a differentiated state, functioning normally as heart cells for a lifetime. When other researchers have tried to stimulate myocardial cells to enter the cell cycle and repair heart muscle, the process gets stuck in G2 and fails to enter M phase. This is the transition that hCdc5 appears to control. By manipulating HCdc5, Bernstein and his colleagues hope to get heart cells to complete their cycle.
"However, there is a lot more to learn about how the hCdc5 protein is regulated, and how it in turn regulates the cell cycle," Bernstein said. Once the genes controlled by hCdc5 are found, he said, they may turn out to regulate the normal progression of the cell from the G2 phase to mitosis. Or they may control the cell's response when DNA is damaged during synthesis, protecting the integrity of the genome by turning off cell division until the damage can be repaired. Also, hCdc5 and similar proteins may regulate genes that were active earlier in the cell cycle, "down-regulating" actions that now need to be turned off.
"If we could use this knowledge about the transcriptional regulation of the normal cell division cycle to stimulate myocardial cells to proliferate, there are experimental methods currently being tested in other labs to deliver the treatment to damaged heart cells," Bernstein said. One possible method would be to package genes for hCdc5 and related proteins inside the shell of a virus that had its own DNA removed. An interventional cardiologist could use a catheter to target delivery of these biological "drugs" to surrounding heart cells, so that they might divide and rejuvenate the damaged tissue.
At the moment, gene therapy of this type remains only a potential option, possibly far in the future. But for cardiologists who work with children, Bernstein said the promise of the science is exciting. "There are many causes of myocardial damage in children," he said. "Some of the most common are coronary artery anomalies that deprive some of the heart muscles of adequate blood supply; congenital lesions; and a lack of oxygen during birth. In pediatric cardiology and cardiac surgery we have made great strides in diagnosing and treating the many profound defects that affect the pediatric heart. But when the heart muscle itself is damaged, right now there is nothing we can do."
Prncipal investigator Harold S. Bernstein, MD, PhD is assistant professor of pediatrics, investigator of the Cardiovascular Research Institute, and member of the UCSF Cancer Center Program in Cell Cycle Disregulation at the University of California, San Francisco. Co-authors for this study are postdoctoral fellow Xiang-He Lei, PhD; graduate fellow Xun Shen and research associate Xiao-qin Xu. Postdoctoral fellow Meihua Chu, Ph.D and collaborator Christoph W. Turck, PhD of the Howard Hughes Medical Institute also are co-authors of a related article being presented at the same Pediatric Academic Societies meeting. A paper on Cdc5-like proteins also will be presented by Bernstein's group at the May 1999 conference, Biochemistry and Molecular Biology '99, "New World Science for the Next Millennium," sponsored by the American Society for Biochemistry and Molecular Biology.
The Bernstein Lab is supported by the Department of Pediatrics and Child Health Research Center at UCSF, as well as grants from the National Heart, Lung, and Blood Institute, the American Heart Association National Center, and the March of Dimes Birth Defects Foundation.
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