DNA Packaging Discovery Reveals Principles by Which CRC Mutations May Cause Cancer (Eagle Group- Nov19, 2012)

The discovery, by Bradley R. Cairns, PhD, Senior Director of Basic Science at HCI and a professor in the Department of Oncological Sciences, is reported in this week's online issue of the journal Nature.

Cairns's research focuses on chromatin remodeling complexes (CRCs), which are cellular protein complexes that behave like motors, expanding or compacting different portions of DNA to either express or silence genes, respectively. Before, scientists thought that the motor within CRCs waits at rest until it receives instructions. Cairns and co-author Cedric R. Clapier show that the motor within a key CRC responsible for gene packaging and assembly is intrinsically turned on, and instead requires specific instructions to turn it off.

"Many articles in the research literature show that CRCs are mutated in cancer cells. They are intimately involved in regulating gene expression -- responsible for correctly packaging genes that control growth proliferation and for unpackaging tumor suppressors," said Cairns. "This research reveals principles by which CRC mutations could cause cancer."

Chromosomes are made of long DNA strands compressed around nodes of protein called nucleosomes; when DNA is compressed, the genes in that area are turned off. Some CRCs, called disassembly CRCs, act as motors that unwind sections of DNA chains, making genes active for a given cell process. Another type, called assembly CRCs, rewinds the DNA chain, recompressing it when the process is complete. The unwind-rewind cycle is repeated continuously throughout a cell's life.

In this study, Cairns and Clapier focused on assembly CRCs. "Before this research, we thought that the motor was off unless a protein coming from another part of the cell turned it on," said Cairns. "Researchers have been searching for the switch by looking at the CRC motor to see what binds to it.

"As it turns out, we discovered that the CRC motor already carries on its flank a 'switch' that inhibits its action until a marker sequence, located on the nucleosome, is encountered. The marker flips the inhibitor switch and allows the CRC to crank the DNA chain back around the nucleosome, promoting gene packaging and silencing" Cairns said. "Our results change where future researchers should be looking to understand how CRCs are regulated -- not at the CRC motor itself, but at the 'switches' that flank the motor."

The study also describes a measuring function on the CRC that checks for the correct distance between one nucleosome and the next, telling the motor to switch off at the proper time, a function needed for gene silencing.

Cairns's lab will now examine this same switching concept in disassembly remodelers. "There are additional remodeler families with alternative functions, like DNA repair," said Cairns. "We think this concept will apply to them as well."

This research was supported by funding from the National Institutes of Health (GM60415 and CA042014) and from the Howard Hughes Medical Institute.

Journal Reference:

1.      Cedric R. Clapier, Bradley R. Cairns. Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature, 2012; DOI:10.1038/nature11625

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The above story is reprinted from materials provided by University of Utah Health Sciences.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of Eagle Group or its staff.

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Reconsidering Cancer's Bad Guy (Eagle Group- Nov 19, 2012)

Researchers at the University of Copenhagen have found that a protein, known for causing cancer cells to spread around the body, is also one of the molecules that trigger repair processes in the brain.

How to repair brain injuries is a fundamental question facing brain researchers. Scientists have been familiar with the protein S100A4 for some time as a factor in metastasis, or how cancer spreads. However it's the first time the protein has been shown to play a role in brain protection and repair.

"This protein is not normally in the brain, only when there's trauma or degeneration. When we deleted the protein in mice we discovered that their brains were less protected and able to resist injury. We also discovered that S100A4 works by activating signalling pathways inside neurons," says Postdoc Oksana Dmytriyeva, who worked on the research in a team at the Protein Laboratory in the Department of Neuroscience and Pharmacology at the University of Copenhagen.

The villain turns out to be the hero

This research stands on the shoulders of many years of work on S100A4 in its deadlier role in cancer progression. The discovery represents a significant development for the new Neuro-Oncology Group that moved to the University of Copenhagen's Protein Laboratory Group from the Danish Cancer Society in October.

"We were surprised to find this protein in this role, as we thought it was purely a cancer protein. We are very excited about it and we're looking forward to continuing our research in a practical direction. We hope that the findings will eventually benefit people who need treatment for neurodegenerative disorders like Alzheimer's disease, although obviously we have a long way to go before we get to that point," says Oksana Dmytriyeva.

The scientific paper The metastasis-promoting S100A4 protein confers neuroprotection in brain injury can be found online in the journal Nature Communications.

Journal Reference:

1.      Oksana Dmytriyeva, Stanislava Pankratova, Sylwia Owczarek, Katrin Sonn, Vladislav Soroka, Christina M. Ridley, Alexander Marsolais, Marcos Lopez-Hoyos, Noona Ambartsumian, Eugene Lukanidin, Elisabeth Bock, Vladimir Berezin, Darya Kiryushko. The metastasis-promoting S100A4 protein confers neuroprotection in brain injury.Nature Communications, 2012; 3: 1197 DOI:10.1038/ncomms2202

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The above story is reprinted from materials provided by University of Copenhagen.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of Eagle Group or its staff.

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Breakthrough Nanoparticle Halts Multiple Sclerosis in Mice, Offers Hope for Other Immune-Related Diseases (Eagle Group-Nov 19, 2012)

The new nanotechnology also can be applied to a variety of immune-mediated diseases including Type 1 diabetes, food allergies and airway allergies such as asthma.

In MS, the immune system attacks the myelin membrane that insulates nerves cells in the brain, spinal cord and optic nerve. When the insulation is destroyed, electrical signals can't be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness. About 80 percent of MS patients are diagnosed with the relapsing remitting form of the disease.

The Northwestern nanotechnology does not suppress the entire immune system as do current therapies for MS, which make patients more susceptible to everyday infections and higher rates of cancer. Rather, when the nanoparticles are attached to myelin antigens and injected into the mice, the immune system is reset to normal. The immune system stops recognizing myelin as an alien invader and halts its attack on it.

"This is a highly significant breakthrough in translational immunotherapy," said Stephen Miller, a corresponding author of the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. "The beauty of this new technology is it can be used in many immune-related diseases. We simply change the antigen that's delivered."

"The holy grail is to develop a therapy that is specific to the pathological immune response, in this case the body attacking myelin," Miller added. "Our approach resets the immune system so it no longer attacks myelin but leaves the function of the normal immune system intact."

The nanoparticle, made from an easily produced and already FDA-approved substance, was developed by Lonnie Shea, professor of chemical and biological engineering at Northwestern's McCormick School of Engineering and Applied Science.

"This is a major breakthrough in nanotechnology, showing you can use it to regulate the immune system," said Shea, also a corresponding author. The paper will be published Nov. 18 in the journal Nature Biotechnology.

Miller and Shea are also members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. In addition, Shea is a member of the Institute for BioNanotechnology in Medicine and the Chemistry of Life Processes Institute.

Clinical Trial for Ms Tests Same Approach -- With Key Difference

The study's method is the same approach now being tested in multiple sclerosis patients in a phase I/II clinical trial -- with one key difference. The trial uses a patient's own white blood cells -- a costly and labor intensive procedure -- to deliver the antigen. The purpose of the new study was to see if nanoparticles could be as effective as the white blood cells as delivery vehicles. They were.

The Big Nanoparticle Advantage for Immunotherapy

Nanoparticles have many advantages; they can be readily produced in a laboratory and standardized for manufacturing. They would make the potential therapy cheaper and more accessible to a general population. In addition, these nanoparticles are made of a polymer called Poly(lactide-co-glycolide) (PLG), which consists of lactic acid and glycolic acid, both natural metabolites in the human body. PLG is most commonly used for biodegradable sutures.

The fact that PLG is already FDA approved for other applications should facilitate translating the research to patients, Shea noted. Miller and Shea tested nanoparticles of various sizes and discovered that 500 nanometers was most effective at modulating the immune response.

"We administered these particles to animals who have a disease very similar to relapsing remitting multiple sclerosis and stopped it in its tracks," Miller said. "We prevented any future relapses for up to 100 days, which is the equivalent of several years in the life of an MS patient."

Shea and Miller also are currently testing the nanoparticles to treat Type one diabetes and airway diseases such as asthma.

Nanoparticles Fool Immune System

In the study, researchers attached myelin antigens to the nanoparticles and injected them intravenously into the mice. The particles entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. There, the particles were engulfed by macrophages, a type of immune cell, which then displayed the antigens on their cell surface. The immune system viewed the nanoparticles as ordinary dying blood cells and nothing to be concerned about. This created immune tolerance to the antigen by directly inhibiting the activity of myelin responsive T cells and by increasing the numbers of regulatory T cells which further calmed the autoimmune response.

"The key here is that this antigen/particle-based approach to induction of tolerance is selective and targeted. Unlike generalized immunosuppression, which is the current therapy used for autoimmune diseases, this new process does not shut down the whole immune system," said Christine Kelley, National Institute of Biomedical Imaging and Bioengineering director of the division of Discovery Science and Technology at the National Institutes of Health, which supported the research. "This collaborative effort between expertise in immunology and bioengineering is a terrific example of the tremendous advances that can be made with scientifically convergent approaches to biomedical problems."

"We are proud to share our expertise in therapeutics development with Dr. Stephen Miller's stellar team of academic scientists," said Scott Johnson, CEO, president and founder of the Myelin Repair Foundation. "The idea to couple antigens to nanoparticles was conceived in discussions between Dr. Miller's laboratory, the Myelin Repair Foundation's drug discovery advisory board and Dr. Michael Pleiss, a member of the Myelin Repair Foundation's internal research team, and we combined our efforts to focus on patient-oriented, clinically relevant research with broad implications for all autoimmune diseases. Our unique research model is designed to foster and extract the innovation from the academic science that we fund and transition these technologies to commercialization. The overarching goal is to ensure this important therapeutic pathway has its best chance to reach patients, with MS and all autoimmune diseases."

Journal Reference:

1.      Daniel R Getts, Aaron J Martin, Derrick P McCarthy, Rachael L Terry, Zoe N Hunter, Woon Teck Yap, Meghann Teague Getts, Michael Pleiss, Xunrong Luo, Nicholas JC King, Lonnie D Shea, Stephen D Miller. Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nature Biotechnology, 2012; DOI:10.1038/nbt.2434

Source:

The above story is reprinted from materials provided by Northwestern University, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of Eagle Group or its staff.

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