Sep. 30, 1999 DURHAM, N.C. -- A gene whose malfunction causes several leukemias normally functions as a "molecular carpenter," Duke pharmacologists have discovered. The gene, called c-Abl, triggers other molecules that construct the internal framework of cells.
According to the scientists, this discovery of c-Abl's normal function could reveal new targets for cancer drugs, and it also hints at a role for c-Abl in the brain, in building nerve cells and aiding their movement.
In an article in the September issue of Genes & Development, the researchers reported that c-Abl is mainly switched on by another protein called Src, which is also known to cause cancer when it malfunctions. Src, in turn, is activated by external growth factors such as PDGF and EGF. Growth factors are substances outside the cell that trigger them to proliferate. Once activated, c-Abl itself acts as a trigger for the cell to reorganize the internal framework, called the cytoskeleton, that gives cells their shape and allows them to move.
"We have long understood many of the things that the oncogenic, or cancer-causing, forms, of c-Abl do," said Ann Marie Pendergast, associate professor of pharmacology and cancer biology, who led the research. "But because we did not know the normal function of c-Abl, we have been missing a critical part of the picture of how the cancer-causing forms take over the cell's machinery. "If we knew how c-Abl functioned normally, we would know more precisely how the oncogenic forms alter cell function."
Lead author on the Genes & Development paper is postdoctoral fellow Rina Pattner, and other authors besides Pendergast are Lisa Kadlec, Kris DeMali and Andrius Kazlauskas. Their work was supported by the National Cancer Institute and by the Glaxo Wellcome Collaborative Program in Cancer Research.
According to Pendergast, studies over the last decade had revealed c-Abl's key role in producing two forms of leukemia--chronic myelogeneous leukemia and acute lymphoblastic leukemia. Basically, these leukemias occur when chromosomes in dividing white blood cells become snipped apart and restitched incorrectly, with the c-Abl gene becoming linked to a gene called BCR that switches c-Abl on, causing the blood cells to proliferate out of control.
However, the normal role of c-Abl remained unknown, despite studies in other laboratories that linked the homolog of c-Abl in fruit flies with the growth of nerve cells and the metabolic pathways governing formation and rearrangement of the cytoskeleton.
In their experiments, the Duke Medical Center researchers basically explored the effects of genetically manipulating mouse cells called fibroblasts to alter the levels of the growth factors and the protein enzymes produced by c-Abl and Src. Both these enzymes are chemical switches called tyrosine kinases, that trigger other proteins by adding a phosphate to the amino acid tyrosine that is part of the protein.
By altering levels of the growth factors and Src, in the mouse cells and observing the effects on c-Abl, the scientists could determine whether they were part of the normal pathway by which c-Abl functioned.
The pharmacologists' measurements revealed that the growth factors and the Src protein did trigger the activity of c-Abl protein. What's more, their studies revealed that the Src added phosphate to the c-Abl protein, the normal action of a kinase triggering another enzyme.
The scientists also found hints of another pathway by which the growth factors activate c-Abl without triggering Src.
Finally, they found that c-Abl was necessary for cells to undergo cytoskeletal reorganization in response to PDGF. For example, when fibroblast cells that lacked c-Abl were "starved" of serum and then the PDGF growth factor was added, they were unable to remodel their cytoskeleton, as revealed by microscopic studies. However, cells with c-Abl did show such remodeling.
"This finding is the very first example of a response to c-Abl activation that can be connected to a biological response," Pendergast said. The work of other researchers showed that neuroepithelial cells derived from mice that lack c-Abl kinases have a disorganized cytoskeleton. This observation implies that c-Abl may have a role in brain cell development and function.
"In general, our findings reveal that c-Abl acts downstream of growth factor receptors, telling us how oncogenic forms of c-Abl take over the normal cell proliferation pathway," Pendergast said. "Importantly, they also show how Src activates c-Abl.
"Since an oncogenic form of Src has been implicated in some advanced colon cancers, it means that drugs now undergoing clinical trials to treat leukemia by blocking c-Abl kinase activity may also be used to treat these colon cancers."
According to Pendergast, the Src and c-Abl metabolic pathways are likely far more complicated and branched than the scientists now understand. So, they have embarked on further studies to trace those pathways, the details of the enzymatic reactions and specifically how the c-Abl protein connects with the proteins that actually construct the cytoskeleton.
"If we succeed, this will be the first demonstration of how a tyrosine kinase actually can control cytoskeleton remodeling, by acting on the specific molecules that actually do the remodeling," Pendergast said.
Also, said Pendergast, the finding of a role for c-Abl kinases in brain function may have clinical implications.
"I think we're going to find that this molecule is important in a lot of basic processes, perhaps including neurodegenerative diseases," she said.
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