March 1, 2006
La Jolla, CA – Mutations in a protein, called APC, that normally functions to suppress the development of tumors, cause 85 percent of all colon cancers, the number two cancer killer in the US. For years, scientists thought they knew how: The normal APC protein destroys a protein called Β-catenin, which turns on genes responsible for cell growth. The mutant APC proteins that are commonly found in colon cancer and melanoma, are not able to destroy Β-catenin, leading to unchecked cell growth.
But that”s only half the story, researchers at the Salk Institute for Biological Studies discovered and reported in the March 1st issue of Genes and Development. They uncovered an additional role for APC: APC actually follows Β-catenin into the nucleus of the cell and acts directly to switch off the expression of the growth control genes. The cancer-associated mutant APC proteins fail to turn off these genes.
The study was led by Salk professor Katherine A. Jones, Ph.D., a professor in the Regulatory Biology Laboratory, and postdoctoral researchers Jose Sierra, Ph.D., and Tomonori Yoshida, Ph.D.
“When Β-catenin goes into the cell’s nucleus to activate a gene, something needs to control it’s actions and make sure that the growth-control genes are turned on only briefly,” explains Jones. “Part of what APC does is to inactivate or destroy Β-catenin right at the DNA, but we found that it does more than that;it also marks the gene in a way that will keep it inactive. Without this check, the growth control genes simply cannot be shut down,” she adds.
APC and Β-catenin are part of the Wnt signaling pathway, which plays a crucial role in many biological processes, such as embryonic development and cell proliferation. The Wnt signaling pathway is activated when Wnt proteins bind to receptor molecules protruding from the cell surface. A cascade of intracellular relay components then passes the signal to Β-catenin, which can enter the cell’s nucleus. There, it turns on genes that are involved in cell division, such as c-myc. Inappropriate activation of this signaling cascade promotes uncontrolled cell proliferation, often the first step towards the development of cancer.
“The APC-induced degradation of Β-catenin was thought to be the main shut-off mechanism, but we discovered that APC has an additional role inside the nucleus”, says Sierra, one of the first authors. “It works like a switch that shuts off c-Myc and other Wnt-regulated genes by pushing Β-catenin off the DNA and recruiting a repressor molecule that hunkers down in Β-catenin’s place,” he explains.
“But only full-length APC molecules are up to the task,” says Jones. She compares it to a double whammy. “Truncated APC molecules found in colorectal cancer cells not only fail to degrade Β-catenin but are also unable to shut down the c-Myc gene once it”s activated.”
If stretched out, the DNA of a single human cell would form a very thin thread about 6 feet in length. To fit such a long molecule inside a cell”s nucleus and keep everything neatly organized, the DNA is threaded around histone proteins and coiled up in a highly condensed structure called chromatin. When genes are turned on, to serve as templates for proteins, the tightly folded chromatin must open up just enough to give access to enzymes that read the encoded genetic information. Adding chemical modifications to histones in a process called methylation gives the signal to unfurl the tightly packed chromatin.
“Another part of this study was that we discovered that Β-catenin actively recruits an enzyme that methylates histones,” says co-first author Yoshida. “Methylation of histones plays a very important role in marking active genes, but in the case of Β-catenin, it wasn”t clear how the necessary enzymes are called in,” he adds.
When Β-catenin”s job is done, APC swoops in with repressors in tow that counteract this open chromatin state, and mark down ” “catenin for destruction. “Scientists are beginning to realize that these proteins don”t often move around inside the cell by themselves, but rather are accompanied by a whole entourage of co-activators, co-repressors, binding factors and other players,” says Jones, “and there”s a lot of multi-tasking going on”.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.