Two proteins that scientists once thought carried out the same functions are actually antagonists of each other, and keeping them in balance is key to preventing diseases such as cancer, according to new findings published in the February 25 issue of Developmental Cell by scientists at Fox Chase Cancer Center. The results suggest that new compounds could fight cancer by targeting the pathways responsible for maintaining the proper balance between the proteins.
"It's our job now to understand how we can intervene therapeutically in this system, so we can restore balance when it's thrown off," says study author David L. Wiest, PhD, professor and deputy chief scientific officer at Fox Chase.
The two proteins—"Rpl22" and "Rpl22-like1", which contribute to the process by which additional cellular proteins are made—are created from two similar genes, leading researchers to previously believe they were performing identical functions in the body. "What we're finding is that is absolutely not true," says Wiest. "Not only are they performing different functions, they are antagonizing each other."
During the study, Wiest and his team knocked out Rpl22 in zebrafish—a common model of human disease. Without Rpl22, the zebrafish don't develop a type of T cells (a blood cell) that helps fight infections. The same developmental defect was observed when they knocked out Rpl22-like1, indicating that both proteins are independently required to enable stem cells to give rise to T cells.
But when the researchers tried to restore T cells in zebrafish that lacked Rpl22 by adding back Rpl22-like1, it didn't work. The reverse was also true—Rpl22 was not enough to restore function after the researchers eliminated Rpl22-like1. These results led Wiest and his team to believe that, although the proteins are both involved in producing stem cells, they do not perform the same function.
To learn more about the proteins' individual functions, the researchers looked at the levels of different proteins involved in stem cell production when either Rpl22 or Rpl22-like1 was absent. Without Rpl22-like1, cells had lower levels of a protein known as Smad1—a critical driver of stem cell development. And when Rpl22 disappeared, levels of Smad1 increased dramatically.
Both proteins can bind directly to the cellular RNA from which Smad1 is produced, suggesting that they maintain balance in stem cell production via their antagonistic effects on Smad1 expression, explains Wiest.
"I like to think of Rpl22 as a brake, and Rpl22-like1 as a gas pedal – in order to drive stem cell production, both have to be employed properly. If one or the other is too high, this upsets the balance of forces that regulate stem cell production, with potentially deadly effects," says Wiest.
Specifically, too much Rpl22 (the "brake"), and stem cell production shuts off, decreasing the number of blood cells and leading to problems such as anemia. Too much Rpl22-like1 (the "gas pedal"), on the other hand, can create an over-production of stem cells, leading to leukemia.
Previous research has found that Rpl22-like1 is often elevated in cancer, including 80% of cases of acute myeloid leukemia (AML). Conversely, researchers have found that in other cancers, the gene that encodes Rpl22 is deleted. "Either one of these events is sufficient to alter the balance in stem cell production in a way that pushes towards cancer," says Wiest.
Co-authors on the study include Yong Zhang, Anne-Cécile E. Duc, Shuyun Rao, Xiao-Li Sun, Alison N. Bilbee, Michele Rhodes, Qin Li, Dietmar J. Kappes, and Jennifer Rhodes of Fox Chase.
Fox Chase Cancer Center, part of Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation's first cancer hospitals, Fox Chase also was among the first institutions to receive the National Cancer Institute's prestigious comprehensive cancer center designation in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are routinely recognized in national rankings, and the Center's nursing program has achieved Magnet status for excellence three consecutive times. Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research and oversees programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX-CHASE (1-888-369-2427) or visit www.foxchase.org.
Diana Quattrone | EurekAlert!
Locusts at the wheel: University of Graz investigates collision detector inspired by insect eyes
07.10.2015 | Karl-Franzens-Universität Graz
Flipping molecular attachments amps up activity of CO2 catalyst
06.10.2015 | DOE/Brookhaven National Laboratory
Für die MICADO-Kamera, das Instrument mit dem das European Extremely Large Telescope (E-ELT) seine ersten Bilder machen wird, beginnt eine neue Phase: In einer gemeinsamen Absichtserklärung (Memorandum of Understanding) auf der „Kick-off“-Konferenz in Wien bestätigten die Partner in Deutschland, Frankreich, den Niederlanden, Österreich und Italien ihre Teilnahme am Projekt. Zwei Wochen zuvor, am 18. September, hatten das Konsortium und die Europäische Südsternwarte (ESO), die das Teleskop baut, den entsprechenden Kooperationsvertrag unterzeichnet. Nach diesen Meilensteinen tritt das Projekt nun in die Designphase ein.
Als erste, dedizierte Kamera für das E-ELT wird MICADO beugungsbegrenzte Abbildungen bei Nah-Infrarot-Wellenlängen (Wärmestrahlung) mit dem Riesenteleskop...
The MICADO camera, a first light instrument for the European Extremely Large Telescope (E-ELT), has entered a new phase in the project: by agreeing to a Memorandum of Understanding, the partners in Germany, France, the Netherlands, Austria, and Italy, have all confirmed their participation. Following this milestone, the project's transition into its preliminary design phase was approved at a kick-off meeting held in Vienna. Two weeks earlier, on September 18, the consortium and the European Southern Observatory (ESO), which is building the telescope, have signed the corresponding collaboration agreement.
As the first dedicated camera for the E-ELT, MICADO will equip the giant telescope with a capability for diffraction-limited imaging at near-infrared...
Self-driving cars will be on our streets in the foreseeable future. In Graz, research is currently dedicated to an innovative driver assistance system that takes over control if there is a danger of collision. It was nature that inspired Dr Manfred Hartbauer from the Institute of Zoology at the University of Graz: in dangerous traffic situations, migratory locusts react around ten times faster than humans. Working together with an interdisciplinary team, Hartbauer is investigating an affordable collision detector that is equipped with artificial locust eyes and can recognise potential crashes in time, during both day and night.
Inspired by insects
Selbstfahrende Autos könnten in absehbarer Zukunft auf unseren Straßen unterwegs sein. Ein innovativer Fahrzeugassistent, der bei Kollisionsgefahr das Steuer übernimmt, wird gerade in Graz erforscht. Manfred Hartbauer vom Institut für Zoologie der Karl-Franzens-Universität hat sich die Basis dafür in der Natur abgeschaut: Wanderheuschrecken können in brenzligen Verkehrssituationen etwa zehnmal schneller reagieren als Menschen. In Zusammenarbeit mit einem interdisziplinären Team erforscht er einen kostengünstigen Kollisionsdetektor, der mit künstlichen Heuschrecken-Augen ausgestattet ist und drohende Zusammenstöße bei Tag und Nacht rechtzeitig erkennen kann.
Ein interdisziplinäres Forscherteam hat den ersten Prototyp eines Miniatur-Teilchenbeschleunigers gebaut, der mit Terahertz- anstelle von Hochfrequenz-Strahlung funktioniert. Ein einzelnes Beschleunigungsmodul ist dabei nur 1,5 Zentimeter lang und einen Millimeter dünn. Die Terahertz-Technik verspricht eine Miniaturisierung um mindestens den Faktor 100, wie die Wissenschaftler um DESY-Forscher Franz Kärtner vom Center for Free-Electron Laser Science (CFEL) betonen. Sie stellen ihren Prototyp im Fachblatt „Nature Communications“ vor. Das CFEL ist eine Kooperation von DESY, Universität Hamburg und Max-Planck-Gesellschaft.
Für kompakte Terahertz-Beschleuniger sehen die Autoren zahlreiche Anwendungen in Materialforschung, Medizin und Teilchenphysik sowie bei Röntgenlasern....
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