How a cancer-killing gene may actually work
Posted: May 29, 2014 at 2:47 am
Scientists armed with a supercomputer and a vast trove of newly collected data on the body's most potent "tumor suppressor" gene have created the best map yet of how the gene works, an accomplishment that could lead to new techniques for fighting cancers, which are adept at disabling the gene in order to thrive.
Scientists from the University of Colorado Cancer Center and the University of Colorado Boulder used a new technology to tease out how the p53 gene -- which is responsible for recognizing damaged DNA in cells and then marking them for death -- is actually able to suppress tumors by determining what other genes p53 regulates. The study, published in the journal eLife, describes dozens of new genes directly regulated by p53.
The study authors say further research can explore which of these genes are necessary for p53's cancer-killing effect, how cancer cells evade these p53-activated genes, and how doctors may be able to moderate cancer cells' ability to stay safe from these genetic attempts at suppression.
The exhaustively studied p53 gene -- which has been the subject of 50,000 papers over more than 30 years of research -- is the most commonly inactivated gene in cancers. When p53 acts, cells are stopped or killed before they can survive, grow, replicate and cause cancer.
As such, all cancers must deal with p53's anti-tumor effects. Generally, there are two ways that cancer cells do this: by mutating p53 directly or by making a protein called MDM2, which stops p53 from functioning
The current study explores cancer cells' second strategy of blocking p53 function by producing the protein MDM2. Researchers have reasoned that treating a patient with an MDM2 inhibitor should allow p53 to restart its anti-cancer activities.
"MDM2 inhibitors, which are through phase I human trials, effectively activate p53 but manage to kill only about one-in-20 tumors," said Joaqun Espinosa, an investigator at the CU Cancer Center, an associate professor of molecular, cellular and developmental biology at CU-Boulder, and the paper's co-senior author. "The question is why. What else is happening in these cancer cells that allow them to evade p53?"
The answer is in what are called "downstream" effects of this gene, Espinosa said. The gene p53 doesn't act against cancer alone. Instead, it is the master switch that sets in motion a cascade of genetic events that lead to the destruction of cancer cells. And until now, it was unclear exactly which other genes were directly activated by p53.
The imperfect knowledge of p53's effects isn't for lack of research interest. Researchers have written thousands of papers exploring p53's targets and, in fact, many genetic targets are previously known. Most of these studies determine genetic targets by measuring levels of RNA.
When a gene is activated, it creates a protein. But between the gene and its protein product is the measurable step of RNA -- the more gene-specific RNA, the more often a gene's informational blueprint is carried to the cell's manufacturing centers, and the more protein is eventually made. Researchers measure RNA to see which genes are being turned up or down by any other gene.