Dartmouth Medical School geneticists have discovered a striking turnabout role for a gatekeeper known to put on the brakes for colon cancer. Flaws in a gene called adenomatous polyposis coli (APC), which normally prevents excessive cell growth, are thought to trigger development of most colorectal cancers.
But in an about face, the tumor suppressor gene also has a second task, the researchers found, as a gas pedal that accelerates signaling between cells. This novel duality is reported in the January 18 issue of Science by a team led by Dr. Yashi Ahmed, assistant professor of genetics at DMS.
“Colon cancer is the second most frequent cause of cancer-related death in the United States,” said Ahmed. “Understanding the normal role of APC and what’s happening to cells that have lost the gene can help us identify therapeutic targets for drug action against this common cancer.”
APC was first identified in families with a hereditary predisposition to develop colon cancer. Family members are born with an error in one of their two APC gene copies, but are fine as long as the other gene copy is normal. However, many of their colon cells develop a second defective gene. As a result, by their teens and twenties these individuals get hundreds to thousands of colon growths--called polyps--some of which invariably progress to cancer, so their colon is usually removed when they are in their twenties.
But these types of polyps that have a strong association with cancer are not limited to hereditary colon cancer. By age 60, according to Ahmed, up to 40 percent of the general population will have at least one such polyp with mutations in both APC genes. Fortunately, with a colonoscopy to view the colon many polyps can be removed in their early stages, before they become cancer.
APC is part of a vital signaling pathway that coordinates cell growth in all animals—from flies through people. During embryonic development, this pathway causes cells to grow and differentiate to become the kind of cells they should be. In many adult cells, however, the pathway should be turned off, and APC puts the brakes on the pathway to stop cell growth.
The researchers devised strategies to explore the molecular workings of APC in the fruit fly, a simple animal with rapid breeding time that offers many advantages in the laboratory. When they remove or reduce APC, they see fruit flies with no wings, peculiar abdomens and many other oddities.
However, APC defects found in colonic polyps have an unusual feature. Generally, gene mutations can disrupt an entire protein, but in colon cancers, only half the APC protein is lost, while the other half remains, Ahmed explains. Her work in fruit flies suggests a reason for this unexplained phenomenon.
“We found that APC has a second, new job. It not only puts the brake on cell signaling, but also gives some gas. These two functions are controlled by different parts of the protein. In the colon cancers, the brake part of the APC protein is lost, but there is strong pressure to retain the give-it-some-gas portion,” Ahmed said.
Indeed, the DMS team’s data suggest that this new “gas” facet is also present in the human APC protein, reinforcing APC’s role as a regulator that promotes or suppresses cell growth. Future studies on how APC balances signals may help benefit treatments not only for colon tumors, but also for birth defects, since the signaling pathway regulated by APC affects nearly all tissues during development.
Hali Wickner | EurekAlert!
Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie
Study overturns seminal research about the developing nervous system
21.04.2017 | University of California - Los Angeles Health Sciences
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...
Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.
A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
21.04.2017 | Physics and Astronomy
21.04.2017 | Health and Medicine
21.04.2017 | Physics and Astronomy