Feb. 1, 2001 Philadelphia -- The BRCA2 gene, linked to familial breast and ovarian cancers, plays an important and previously unsuspected role in human cell division, according to a new study by scientists at The Wistar Institute. When the BRCA2 protein is inactivated, their experiments showed, cells are dramatically delayed in their progress through mitosis, the cell-division stage of the cell cycle. The find opens an entirely new line of thinking for researchers working to understand how BRCA2 can cause cancer when mutated. With fresh insights may come more effective, more targeted treatments.
The same study also identified a new gene, dubbed BRAF35, and established that the BRAF35 protein associates closely with BRCA2 in a previously unknown complex. As with BRCA2, when the BRAF35 protein is inactivated, progress through mitosis is significantly delayed, raising the question of whether BRAF35, too, might be responsible for some cancers. Indeed, the BRAF35 gene maps to a location on chromosome 19 where anomalies have reported in many ovarian cancers.
A report on the study appears in the January 26 issue of Cell.
"This study helps us not only to better understand what BRCA2 is doing, but it also identifies a new gene, BRAF35, that may be involved in breast and ovarian cancers," says Wistar assistant professor Ramin Shiekhattar, Ph.D., senior author on the study. "It provides researchers with a number of new places to look for answers to our questions about these cancers."
Previous studies of BRCA2 had suggested that the gene was involved in DNA repair, not cell division. Shiekhattar's findings do not argue with those earlier observations, but offer an additional scientific framework within which to explore BRCA2 and its function.
"The complex in which we find BRCA2 and BRAF35 might serve a dual purpose for the cell," Shiekhattar notes. "It could be involved in both processes, DNA repair and cell cycle progression. Evolution often finds a way to use these complexes as tools for more than one task, like an Allen wrench or a Swiss Army knife."
To establish that BRCA2 and BRAF35 are important in cell cycle progression, the scientists sought first to synchronize the replication cycle in a population of cells. To do this, they used a drug to arrest all of the cells at the same point in the cell division process, then removed the drug. They then neutralized the activity of BRCA2 and BRAF35 using customized antibodies specific to each of the proteins. Between 450 and 600 individual cells were injected with the antibodies in the experiments. They then compared these cells to control cells.
In the control cells, the researchers saw that 12 hours after removal of the synchronizing drug, about 80 percent of the cells had successfully moved through mitosis. But in both the BRCA2- and BRAF-neutralized cells, approximately 50 percent of the cells had been unable to progress through mitosis at the 12-hour mark.
Looking again at 14 hours, the scientists saw that about 90 percent of the experimental cells had moved through mitosis by then. A larger proportion of the neutralized cells continued to lag behind their control counterparts, but this figure did bring the experimental cells closer to the status of the control cells at that time mark. A kind of catch-up effect seemed to be in play.
"Interestingly, the effect of neutralizing these two proteins was a significant delay in mitosis, but it was not a full block of the cell-division process," says Shiekhattar. "The fact that both antibodies appeared to be doing exactly the same thing gave credence to the idea of a functional interaction between these two proteins and indicated they were involved in the same process."
The lead author on the study is Lihua Y. Marmorstein, Ph.D., of The Wistar Institute. The co-authors at Wistar are Alexander Kinev, Ph.D., Daniel A. Bochar, Ph.D., and Hideo Beniya, Ph.D.. Gordon K.T. Chan and Tim J. Yen of Fox Chase Cancer Center are co-authors, as is Jonathan A. Epstein with the University of Pennsylvania School of Medicine. Funding for the research was provided by The V Foundation and The W.W. Smith Charitable Trust.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the basic mechanisms underlying major diseases, including cancer and AIDS, and to developing fundamentally new strategies to prevent or treat them. The Institute is a National Cancer Institute-designated Cancer Center - one of the nation's first, funded continuously since 1968, and one of only ten focused on basic research. Founded in 1892, Wistar was the first institution of its kind devoted to medical research and training in the nation.
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