The protein, named YAP, is linked to the NF2 tumor suppressor gene via a relay of chemical signals that is responsible for shaping and sizing tissue growth by coordinating control of cell proliferation and death, according to research published July 19 in Developmental Cell.
The study provides strong evidence that YAP someday could serve as a therapeutic target for those afflicted by the ringing ears, hearing loss and cataracts that characterize neurofibromatosis type 2, which develops when the NF2 gene malfunctions, according to Duojia Pan, Ph.D., a professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and an investigator of the Howard Hughes Medical Institute.
Pan’s lab has long been exploring the signaling pathway known as Hippo, a collective of biochemically linked proteins that functions like a chain reaction in everything from flies and mice to humans in order to keep organs appropriately sized by relaying a “stop growing” message.
It was in 2003 that Pan’s team identified the gene they named Hippo when they saw that an abnormal copy of it led to an unusually large eye in a developing fruit fly. Two years later, they established that Hippo sits in the middle of a succession of signals working together to limit the expression of genes that otherwise promote cell division and cell survival. In 2007, they showed that by genetically manipulating the hippo pathway in a mouse liver, the organ grew to five times its normal size and became cancerous.
The new experiments not only reveal the mechanism of a disease gene — recent studies estimate that the incidence of neurofibromatosis type 2 may be as high as 1 in 25,000 people — but also move researchers closer to putting their hands on Hippo’s trigger, where Pan thinks “the key to organ size control lies.”
The team discovered the YAP-NF2 link by studying mice that had been genetically altered so that their livers were missing the NF2 protein.
“We found out that mutatating NF2 in mouse liver leads to tumor formation,” Pan says. “The liver lacking NF2 was profoundly enlarged by tumors, the same as those in which we previously had perturbed the Hippo pathway.”
The hypothesis was that NF2, via the Hippo pathway, suppresses YAP, Pan explains: If removing NF2 resulted in too much YAP, which caused liver tumors, then getting rid of YAP should correct the problem.
To test this, the team genetically altered those mice whose livers were missing the NF2 protein by breeding them to mice that enabled the silencing of the YAP gene. Some of the progeny had no NF2 and no YAP. As a byproduct, the same breeding also produced some progeny that had no NF2 and 50 percent of YAP activity.
“We found we could correct the problem by shutting down YAP,” Pan said, “and more than that, we were surprised to discover that even just tamping down the YAP activity by 50 percent resulted in largely normal-looking liver tissue.”
The team showed that when they decreased the YAP protein by 50 percent in the liver of a normal mouse (with no NF2 mutation), no abnormal consequences resulted. However, when they did the same in the context of having removed NF2, the happy consequence was that the liver was appropriately sized and tumor free.
“The exquisite sensitivity of the NF2-deficient tumors to YAP was striking,” Pan says. “This is very powerful, positive data, which we discovered by accident during the process of breeding the mutant mice.”
“This matter of sensitivity makes YAP an important potential therapeutic target,” Pan says. “The level of YAP is very critical for NF2-related tumor development. If someone made a drug to target this protein, it only has to be potent enough to weaken its activity by 50 percent to see a consequence.”
Authors from the Johns Hopkins University School of Medicine, in addition to Pan, are Nailing Zhang, Haibo Bai, Karen K. David, Jixin Dong, Yonggang Zheng, Jing Cai and Robert A. Anders. Other authors are Marco Giovannini, House Ear Institute, and Pentao Liu, The Wellcome Trust Sanger Institute.
Funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, Department of Defense and Howard Hughes Medical Institute.On the Web:
Maryalice Yakutchik | Newswise Science News
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy