Scientists at the University of California San Franciscohave discovered a transcription factor that regulates partof the cycle that makes new copies of the cells in the humanbody. As more specifics are identified about the role ofthis and related cell cycle regulators, the knowledge maylead to new ways to stimulate repair of heart muscle cellsafter damage caused by a heart attack or birth defects.
Harold S. Bernstein, MD, PhD, assistant professor ofpediatrics and investigator at the UCSF CardiovascularResearch Institute, reported on his research group'sdiscoveries about human Cdc5 (hCdc5) on May 2 at thePediatric Academic Societies' 1999 annual meeting in SanFrancisco.
The research, supported in part by the March of Dimes, is inits early stages. "The reason we are so interested in thecell cycle is that we need better treatments for childrenwhose heart muscle is damaged due to heart abnormalities --the most common form of birth defect." Bernstein said. Ifthe work leads to a way to stimulate heart muscle repair, italso could help the 900,000 American adults struck with aheart attack each year. And because hCdc5 appears toregulate a crucial point in the cycle when cell duplicationeither halts or continues, knowledge about its actions coulduncover potential new targets for drugs to stop theuncontrolled cell division in cancer.
Using recombinant DNA techniques, Bernstein cloned hCdc5 in1997 and showed that it is a novel human protein involved inthe division of human cells. Since then, he and his researchteam have shown that it binds to DNA and acts as atranscription factor -- it regulates genes that instruct acell to start the final phase of cell division. Bernsteinand the University of California have obtained a patentprotecting the use of hCdc5 for therapeutic approaches tocancer and muscle disease.
In their presentation to the Society for Pediatric Research,Bernstein's team reports on work to identify specific siteson the human genome where the transcription factor may bind. "Once we identify the genes that hCdc5 and similartranscription factors regulate, a new group of targets forcontrolling cancer and for regeneration of myocardial(heart) cells may be revealed," Bernstein said.
As a pediatric cardiologist, Bernstein is interested in celldivision because heart cells normally do not divide. Infetal life, the heart takes shape and grows by adding morecells, but within weeks after birth every myocardial cellhas stopped dividing. Every cell contracts with each heartbeat, 60-120 times a minute -- by Bernstein's estimate,about 4 billion beats in a lifetime. But like the brain, theheart's cells do not divide and thus cannot repair damagedtissue after an injury.
In many other mammalian organs, cells replenish themselvesand repair damage by re-entering the cell cycle. In thiscycle, the cell stays for some time in a phase called G1 asit prepares to duplicate its content of DNA. Next it entersa phase called S for synthesis, when the DNA in its nucleusis replicated and the copied DNA is checked for mistakes. Ina third phase, G2, further checking goes on and repairs aremade. Finally, assuming the cell passes its own internalquality control mechanisms, the M phase -- mitosis --divides the DNA equally between two daughter cells.
Some cells, such as skin or blood cells, undergo this cycleregularly. Others, such as muscle cells, can be stimulatedto shift from normal, specific functioning into cellreplication as needed for damage repair.
Myocardial cells remain permanently in a differentiatedstate, functioning normally as heart cells for a lifetime.When other researchers have tried to stimulate myocardialcells to enter the cell cycle and repair heart muscle, theprocess gets stuck in G2 and fails to enter M phase. This isthe transition that hCdc5 appears to control. Bymanipulating HCdc5, Bernstein and his colleagues hope to getheart cells to complete their cycle.
"However, there is a lot more to learn about how the hCdc5protein is regulated, and how it in turn regulates the cellcycle," Bernstein said. Once the genes controlled by hCdc5are found, he said, they may turn out to regulate the normalprogression of the cell from the G2 phase to mitosis. Orthey may control the cell's response when DNA is damagedduring synthesis, protecting the integrity of the genome byturning off cell division until the damage can be repaired. Also, hCdc5 and similar proteins may regulate genes thatwere active earlier in the cell cycle, "down-regulating"actions that now need to be turned off.
"If we could use this knowledge about the transcriptionalregulation of the normal cell division cycle to stimulatemyocardial cells to proliferate, there are experimentalmethods currently being tested in other labs to deliver thetreatment to damaged heart cells," Bernstein said. Onepossible method would be to package genes for hCdc5 andrelated proteins inside the shell of a virus that had itsown DNA removed. An interventional cardiologist could use acatheter to target delivery of these biological "drugs" tosurrounding heart cells, so that they might divide andrejuvenate the damaged tissue.
At the moment, gene therapy of this type remains only apotential option, possibly far in the future. But forcardiologists who work with children, Bernstein said thepromise of the science is exciting. "There are many causesof myocardial damage in children," he said. "Some of themost common are coronary artery anomalies that deprive someof the heart muscles of adequate blood supply; congenitallesions; and a lack of oxygen during birth. In pediatriccardiology and cardiac surgery we have made great strides indiagnosing and treating the many profound defects thataffect the pediatric heart. But when the heart muscle itselfis damaged, right now there is nothing we can do."
Prncipal investigator Harold S. Bernstein, MD, PhD isassistant professor of pediatrics, investigator of theCardiovascular Research Institute, and member of the UCSFCancer Center Program in Cell Cycle Disregulation at theUniversity of California, San Francisco. Co-authors for thisstudy are postdoctoral fellow Xiang-He Lei, PhD; graduatefellow Xun Shen and research associate Xiao-qin Xu.Postdoctoral fellow Meihua Chu, Ph.D and collaboratorChristoph W. Turck, PhD of the Howard Hughes MedicalInstitute also are co-authors of a related article beingpresented at the same Pediatric Academic Societies meeting. A paper on Cdc5-like proteins also will be presented byBernstein's group at the May 1999 conference, Biochemistryand Molecular Biology '99, "New World Science for the NextMillennium," sponsored by the American Society forBiochemistry and Molecular Biology.
The Bernstein Lab is supported by the Department ofPediatrics and Child Health Research Center at UCSF, as wellas grants from the National Heart, Lung, and BloodInstitute, the American Heart Association National Center,and the March of Dimes Birth Defects Foundation.
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