Johns Hopkins researchers have found a way to fix "broken" copies of p53, a gene that normally stops the development of pre-cancerous and cancerous cells.
Using yeast cells genetically engineered to include p53 with mutations common to human cancers, Hopkins scientists identified spots in the gene where a second mutation could restore much of its function.
"If we can learn to fix the protein from this gene in human tumors, it should make the tumor cells much more treatable," says Jef Boeke, Ph.D., professor of molecular biology and genetics.
Boeke says the yeast cells he used in the study could provide a rapid, inexpensive model for testing drug treatments designed to restore p53.
With funding from the National Institutes of Health and the W.W. Smith Charitable Trust, Boeke's group, led by Rainer K. Brachmann, M.D., transplanted copies of human p53 with common "point" mutations--changes of one character in the genetic code--into yeast cells.
The yeast cells with p53 are set up so that when p53 works, the cells grow.
With the mutated p53 in place, the yeast cells did not grow. But when Boeke's team caused a small percentage to mutate, a few cells (less than one in a million) started to grow again. Researchers isolated these cells and identified second small mutations that restored p53 function.
"Essentially, we let the yeast cells do the work for us," Boeke jokes. "They found the right places where a genetic tweak to p53 could bring it back to life."
"To prove that this wasn't just an artifact of our yeast system, we then put the p53 genes back in human cell lines," Boeke says. "They worked well--not quite as well as original p53, but pretty close."
Their findings are published in the April issue of The EMBO (European Molecular Biology Organization) Journal. Other authors were Kexin Yu and Yolanda Eby of Hopkins, and Nikola Pavletich, Ph.D., now at Memorial Sloan-Kettering. Brachmann is now at Washington University in St. Louis.
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