University researchers are searching for ways to cripple a renegade gene that may lead to several forms of cancer.
Formed from fragments of two normal chromosomes (see graphic), the Philadelphia chromosome permanently activates a protein-producing cycle, creating an excess of several proteins that frequently lead to cancer.
Learning to control these kinds of activation mechanisms is an integral part of current cancer research, because most forms of cancer result when mutations alter the delicate balance of proteins that control cell replication.
"When a normal cell loses control of this aspect, then when they activate... they become abnormal growths and lead to cancer," said Xiao-Fan Wang, assistant professor of pharmacology, who works with a team of researchers investigating the cellular processes underlying cancer.
Duke scientists are currently trying to learn more about how to stop genes like those on the Philadelphia chromosome that are perpetually activated.
Ann Marie Pendergast, assistant professor of pharmacology, has been working with the activation mechanisms regulating genes that, when mutated, may cause cancer.
Normally, molecular triggers control when genes start and stop producing proteins, but in the Philadelphia chromosome, a retrovirus tampers with the system. As a result, the cell cannot stop the gene from producing proteins.
In these cells, the Philadelphia chromosome produces excess amounts of a protein called GRB-2. GRB-2 molecules combine to form intermediate proteins that, in turn, make RAS, a protein which has been implicated in the development of many forms of cancer. In addition, cells with the Philadelphia chromosome have protective effects from DNA damaging drugs and chemotherapy.
"It's pretty amazing--you get two things that shouldn't be together coming together," Pendergast said. "Not only do you have the leukemic cells, but you somehow have cells protected more than normal cells."
In earlier research, Pendergast and her colleagues had found that GRB-2 triggers onco-genes such as the gene that produces RAS.
To block RAS production, scientists have induced mutations in the Philadelphia chromosome that produce a disfigured form of GRB-2. These mutant GRB-2 molecules do not bond to one another as easily, and as a result, fewer intermediate proteins form, drastically reducing the amount of RAS produced.
Duke scientists have created a mutation in the GRB-2 protein that reduces the amount of RAS produced by 90 percent in tissue culture experiments.
Pendergast said her team is working on two approaches to alter the gene that produces the GRB-2 protein. In one technique, called transfection, scientists place the DNA carrying the instructions for the mutation on top of the cells, which absorb the DNA and insert it into the targeted location. The other approach uses retroviruses, which "infect" the cell with the mutation-causing information, thus disabling the dangerous GRB-2 protein.
Eventually, Pendergast said scientists hope to be able to disable cancerous genes in human patients. Before this can be effective, however, researchers will have to develop a viable way to target the sick cells and not destroy healthy cells as well as the cancer.
An article on some of these findings was published in the October issue of Science magazine, and more articles are in the works, Pendergast said.
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