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 Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>