Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Hunt for DNA amplified in cancers uncovers important target gene

09.08.2006
Gene amplification links growth controlling pathway from Drosophila to human cancers

Researchers at Harvard Medical School (HMS) and Massachusetts General Hospital (MGH) have discovered a new cancer-promoting role for a gene potentially involved in breast, liver, and other kinds of cancers. Their discovery that the gene YAP can transform mammary epithelial cells opens the door to understanding how a novel cell growth controlling pathway first discovered in fruit flies might be important in human cancers. This work is published in the Aug. 8 online early edition of the Proceedings of the National Academy of Sciences and will appear in the Aug. 15 print edition.

"We screened the DNA from breast cancer cells for amplifications that are associated with tumor development. The identification of these new potential cancer-causing genes is critical to uncovering novel pathways that drive the conversion of a normal cell to a cancerous one." says senior author Daniel Haber, MD, PhD, the Laurel Schwartz professor of medicine at HMS and MGH and director of the MGH Cancer Center. This research was conducted jointly by Haber's lab and the lab of Joan Brugge, PhD, professor and chair of the Department of Cell Biology at HMS.

Through microarray analysis of a mammary tumor in a BRCA1/p53 deficient mouse model, Haber's group discovered an amplified region of DNA in the mouse breast tumor that contained only one known gene, called YAP.

"A similar region of DNA is also amplified in some human tumors, but this amplified region often contains other genes that are known to promote cell survival," says Haber, who worked with co-authors Jianmin Zhang, PhD, and Gromoslaw Smolen, PhD, both research fellows at MGH. "Thus, whether the YAP gene could play a role in these cancers had been largely ignored. The amplified region we discovered excluded these other genes, which allowed us to focus on YAP as a new candidate."

The YAP gene has an interesting literature associated with it that comes from the fruit fly Drosophila melanogaster. The Drosophila version of the YAP gene, called Yorkie (Yki), functions to promote both cell division and cell survival and is controlled by several other genes called Hippo (Hpo), Salvador (Sav), Warts (Wts), and Mats. The mutation of any of these upstream genes or the overexpression of Yki causes dramatic overgrowth of cells in the Drosophila eye or wing. This coupling of cell division and cell survival is unique – other genes that promote cell division, for example, Myc, also sensitize a cell to death.

"To use the car analogy that is often applied to cancer models, activation of Myc is like stepping on the gas to activate cell division but also lightly tapping on the brakes at the same time, so that should anything go wrong during division, the car can very quickly be stopped, or the cell can be removed by cell death," says first author Michael Overholtzer, PhD, research fellow in cell biology at HMS. "Yki activation, on the other hand, is like stepping on the gas and disabling the brakes at the same time. Such an activity would be thought to be coveted by cancer cells. Therefore these genes, Yki (YAP), Hpo, Sav, Wts, and Mats, most of which were first discovered in the fruit fly, represent a relatively new and exciting pathway that might control human cancers."

Earlier studies on YAP function in human cells did not support the notion that YAP might be a cancer causing gene because its overexpression actually promoted cell death rather than cell survival (like Yki in Drosophila). Nevertheless, due to the amplification of YAP in a mouse breast tumor, Overholtzer and colleagues decided to examine the functions of YAP in a 3D mammary culture model developed in Brugge's lab.

In this model, they grew cells in a 3-dimensional protein matrix rather than in 2-dimensions on plastic, which allows mammary cells to adopt an architecture in culture that is similar to what occurs in the human breast. They had previously uncovered the effects of other genes using this model that would be missed in more conventional 2D models.

Using these 3D cultures, the authors were able to show that the overexpression of YAP caused a dramatic change in cell behavior associated with invasion into the protein matrix. This type of invasive activity is normally associated with strong acting cancer-promoting genes. The authors were further able to show, in 3D cultures and other assays, that YAP overexpression both activated cell growth and inhibited cell death, just as one might have predicted from the studies of Yki in Drosophila.

Moreover, YAP overexpression was able to turn their non-cancerous mammary cells into cancer-like cells in the lab, as evidenced by the ability of YAP expressing cells to grow in soft agar, an assay that measures cancerous potential. Parallel to Overholtzer and colleague's work, the lab of Scott Lowe, PhD, of Cold Spring Harbor, also showed that YAP overexpression could contribute to the development of liver tumors in a mouse model (Cancer Cell, July 2006). Thus, it appears that YAP is indeed a newly identified cancer-causing gene.

"What we would like to understand next is how YAP is controlled by the Hpo-Sav-Wts pathway in human cells", says Overholtzer. "Also, although we found the YAP amplification in a mouse breast tumor, in human cancers this amplicon is actually much more common in other types such as lung, pancreatic, ovarian, and others. Thus it is possible that YAP plays an important role in the development of many different types of cancer."

Leah Gourley | EurekAlert!
Further information:
http://hms.harvard.edu/
http://www.massgeneral.org

More articles from Life Sciences:

nachricht Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Corporate coworking as a driver of innovation

22.11.2017 | Business and Finance

PPPL scientists deliver new high-resolution diagnostic to national laser facility

22.11.2017 | Physics and Astronomy

Quantum optics allows us to abandon expensive lasers in spectroscopy

22.11.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>