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!
How to become a T follicular helper cell
31.07.2015 | La Jolla Institute for Allergy and Immunology
Heating and cooling with light leads to ultrafast DNA diagnostics
31.07.2015 | University of California - Berkeley
Mit ultrakalten Atomen lässt sich ein neuer Materiezustand beobachten, in dem das System nicht ins thermische Gleichgewicht kommt.
Was passiert, wenn man kaltes und heißes Wasser mischt? Nach einer Weile ist das Wasser lauwarm – das System hat ein neues thermisches Gleichgewicht erreicht....
Using ultracold atoms trapped in light crystals, scientists from the MPQ, LMU, and the Weizmann Institute observe a novel state of matter that never thermalizes.
What happens if one mixes cold and hot water? After some initial dynamics, one is left with lukewarm water—the system has thermalized to a new thermal...
Physikern der Universitäten Regensburg und Marburg ist es gelungen, die von einem starken Lichtfeld getriebene Bewegung von Elektronen in einem Halbleiter in extremer Zeitlupe zu beobachten. Dabei konnten sie ein grundlegend neues Quantenphänomen entschlüsseln. Die Ergebnisse der Wissenschaftler sind jetzt in der renommierten Fachzeitschrift „Nature“ veröffentlicht worden (DOI: 10.1038/nature14652).
Die rasante Entwicklung in der Elektronik mit Taktraten bis in den Gigahertz-Bereich hat unser Alltagsleben revolutioniert. Sie stellt jedoch auch Forscher...
Physicists from Regensburg and Marburg, Germany have succeeded in taking a slow-motion movie of speeding electrons in a solid driven by a strong light wave. In the process, they have unraveled a novel quantum phenomenon, which will be reported in the forthcoming edition of Nature.
The advent of ever faster electronics featuring clock rates up to the multiple-gigahertz range has revolutionized our day-to-day life. Researchers and...
Erstmals konnte das chemische Element Lithium in der ausgestoßenen Materie einer Nova nachgewiesen werden. Beobachtungen von Nova Centauri 2013 mit Teleskopen des La Silla-Observatoriums der ESO und in der Nähe von Santiago de Chile helfen bei der Aufklärung des Rätsels, warum so viele junge Sterne mehr von diesem Element enthalten als erwartet. Diese Entdeckung liefert ein seit langem fehlendes Teil im Puzzle der chemischen Entwicklungsgeschichte unserer Galaxie und ist ein großer Fortschritt für das Verständnis des Mischungsverhältnisses der chemischen Elemente in den Sternen unserer Milchstraße.
Das leichte chemische Element Lithium ist eines der wenigen Elemente, das nach unserer Modellvorstellung auch beim Urknall vor 13,8 Milliarden Jahren...
31.07.2015 | Veranstaltungen
30.07.2015 | Veranstaltungen
30.07.2015 | Veranstaltungen
31.07.2015 | Seminare Workshops
31.07.2015 | Seminare Workshops
31.07.2015 | Verkehr Logistik