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!
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy