Sometimes called the "genome guardian" protein known p53 responds to DNA damage or by halting cell division or causing the cell to commit suicide. Anyway, p53 action helps the formation of short-circuit preventing tumor cells that have undergone malignant mutations continue to grow. However, the p53 gene itself may be damaged, which is thought to contribute to the development of half of all cancers. In tomorrow Science , the researchers describe a drug that may be able to restore the normal function of certain mutated p53 proteins and could therefore open the way for a new type of cancer treatment.
To stop cell division or trigger cell suicide, p53 needs to regulate the activity of various genes, which requires that the first bind to DNA regulatory sequences of genes. The researchers found that many mutations that inactivate p53 cause the protein to misfold, producing a three-dimensional conformation without rigid molecule needed for this connection.
Before searching for a molecule capable of bracing aberrant p53 in the proper position to attach to DNA, biologists Farzan Rastinejad cancer and Barbara Foster Pfizer Central Research in Groton, Connecticut, needed to a quick way to tell if a compound worked. They hit on the idea of using a known antibody that recognizes a part of p53 that is exposed only when the protein is in the right conformation. Ultimately, they examined more than 100,000 compounds with antibodies, initially to identify compounds that could increase its binding to p53 normal, then testing them successfully compounds on the mutant p53 in the tube test. Compounds that have taken this test then went to the next phase, in which the group Rastinejad looked to see who could correct a mutant p53 protein in tumor cells in culture. After winnowing the pack further, they showed that the drugs remaining candidates slowed cancer growth in mice.
The results are a first step on the long road to the manufacture of a drug that can be used in humans. Nevertheless, they represent "an exciting proof of principle of what promises to be a new form of therapy," says Bert Vogelstein, a cancer biologist at Johns Hopkins University School of Medicine in Baltimore, Maryland. In addition, Rastinejad adds, because misfolded proteins are involved in other diseases, including Alzheimer's disease, cystic fibrosis and diseases of the brain thought to be caused by infectious proteins called prions, "this approach may relate to a large number of diseases. "
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