Breaking down just a few of the molecular fences that separate them blurs the lines and leads to the inactivation of at least two tumor suppressor genes, according to researchers at the Salk Institute for Biological Studies.
Their findings, published in the May 15, 2009 issue of Molecular Cell, explain how a single event can put a cell well ahead on the road to becoming a tumor cell. "Selectively removing a couple of fence posts jumpstarts a cascade of global changes all over the genome that may eventually lead to cancer," says Beverly Emerson, Ph.D., a professor in the Regulatory Biology Laboratory, who led the study.
Normally, a complex network of accelerators (growth factors) and brakes (tumor suppressors) keeps a tight lid on cell proliferation. Tumors result when changes in the genome activate cancer-causing genes or inactivate tumor suppressor genes that tip this delicate balance in favor of uncontrolled cell growth.
"For a really long time people have been trying to understand how tumor suppressor genes get silenced in cancer," says postdoctoral researcher and first author Michael Witcher. "Now that we have figured out one of the key events that leads to their inactivation, we might be able to exploit this mechanism to develop novel therapies."
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 heterochromatin. In areas of gene activity, the tightly packed chromatin is unfurled just enough to make the DNA accessible to regulatory proteins.
In many different types of cancers, however, including breast, lung, liver, and pancreatic tumors, as well as multiple myeloma and lymphoma, the tumor suppressor p16 gets buried deep inside heterochromatin. As a result, it cannot be read by the transcription machinery and is unable keep watch over cell growth.
Researchers had known for a long time that sometimes p16 is silenced long before a cell turns cancerous, yet why that particular stretch of DNA was flagged with chemical marks and became wound up so tightly that it became inaccessible had remained a mystery.
Most people looked for clues within the immediate vicinity of the gene but came up empty-handed. When Witcher extended his search further upstream, however, he discovered a binding site for CTCF, short for CCCTC-binding factor, which forms the centerpiece of the molecular fence posts that separate heterochromatin from the rest of the genome. "We found that the binding of this protein is lost from several binding sites in numerous types of cancer cells, leading to the collapse of the molecular boundary," he says. "Once the boundary was gone, the adjacent heterochromatin encroached and silenced the nearest gene."
Further experiments revealed that CTCF was missing because it lacked a chemical modification known as "PARlation," lab lingo for poly(ADP-ribosyl)ation, which allows the protein to bind to select sites in the genome. "Without PARlation, CTCF fails to form the complex necessary to regulate p16 and the tumor suppressor RASSF1A and possibly others, explaining why breast cancer cells always contain both silenced p16 and silenced RASSF1A," says Witcher.
"We believe that destabilization of specific chromosomal boundaries or loss of molecular fences through aberrant CTCF function may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers," says Emerson.
For information on the commercialization of this technology, please contact Dave Odelson at 858-453-4100, x 1223 (email@example.com) in the Salk Office of Technology Management and Development.
This work was supported by the Samuel Waxman Cancer Research Foundation and the Canadian Institute of Health Research.
About the Salk Institute for Biological Studies
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused on both discovery and mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Gina Kirchweger | EurekAlert!
Gene therapy shows promise for treating Niemann-Pick disease type C1
27.10.2016 | NIH/National Human Genome Research Institute
'Neighbor maps' reveal the genome's 3-D shape
27.10.2016 | International School of Advanced Studies (SISSA)
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
27.10.2016 | Materials Sciences
27.10.2016 | Physics and Astronomy
27.10.2016 | Life Sciences