Discovery Of New Proteasome Regulatory Mechanism May Have Implications For Neurodegenerative Diseases And Cancer

Main Category: Alzheimer's / Dementia
Also Included In: Cancer / Oncology;??Parkinson's Disease
Article Date: 03 Jul 2013 - 1:00 PDT Current ratings for:
Discovery Of New Proteasome Regulatory Mechanism May Have Implications For Neurodegenerative Diseases And Cancer

Dysfunction of the ubiquitin-proteasome system is related to many severe neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and certain types of cancer. Such dysfunction is also believed to be related to some degenerative muscle diseases.

The proteasome is a large protein complex that maintains cellular protein balance by degrading and destroying damaged or expired proteins. The ubiquitin is a small protein that labels proteins for destruction for the proteasome. If the system does not work effectively enough, expired and damaged proteins accumulate in the cell. If the system is overly active, it destroys necessary proteins in addition to unnecessary ones. In both cases, cell function is disturbed, and the cell may even die.

Proteasome activity is believed to decrease with ageing. However, not much is yet known about how proteasome activity is regulated in an aging multicellular organism. The research team of Academy Research Fellow, Docent Carina Holmberg-Still has discovered an important proteasome regulatory mechanism. The study was published in Cell Reports , a highly esteemed scientific journal.

"We examined whether proteasome activity is affected by insulin/IGF-1 signalling [IIS], which regulates aging in many organisms. The results show that decreased IIS increases proteasome activity," says Holmberg-Still.

Proteasome activity was studied in C. elegans, a free-living roundworm. Decreased IIS increases proteasome activity through the FOXO transcription factor DAF-16 and the UBH-4 enzyme. DAF-16 represses the expression of ubh-4 in certain cell types. The ubh-4 enzyme slows proteasome activity, which means that its repression accelerates proteasome activity.

"Using a cell culture model, we proved that the same mechanism works in human cells," says Holmberg-Still. When the expression of the uchl5 enzyme - the human equivalent of ubh-4 - was decreased, proteasome activity and the degradation of harmful proteins increased.

"Our study shows that the effect of ageing and the related signalling pathway on proteasome activity is tissue-specific. This was a new and interesting discovery that bears great significance in terms of treatment opportunities," says researcher Olli Matilainen, who prepared his dissertation in Holmberg-Still's research team.

The identification of proteins that regulate proteasome activity and an understanding of the regulatory mechanism offer new opportunities in treating diseases that involve proteasome dysfunction. According to Holmberg-Still, proteins that regulate proteasome activity are particularly interesting in terms of medicine development.

"An ability to accelerate proteasome activity could be beneficial in the treatment of neurodegenerative diseases. Targeted proteasome inhibitors would be useful in the treatment of cancer - general proteasome inhibitors are already used as cancer medication to some extent, but they often have harmful side effects, because they cannot be targeted to a specific tissue."

Holmberg-Still's team continues to investigate tissue-specific mechanisms that regulate proteasome activity. The team collaborates with clinical researchers to confirm whether its research results can be refined for clinical use.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our alzheimer's / dementia section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University of Helsinki. "Discovery Of New Proteasome Regulatory Mechanism May Have Implications For Neurodegenerative Diseases And Cancer." Medical News Today. MediLexicon, Intl., 3 Jul. 2013. Web.
5 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Discovery Of New Proteasome Regulatory Mechanism May Have Implications For Neurodegenerative Diseases And Cancer'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam)

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

Understanding of complex diseases likely to improve following the unexpected discovery of the ways Cells Move

Main category: Cancer / Oncology
Also included in: respiratory / asthma;??Biology / biochemistry
Article Date: June 25, 2013 - 1:00 PDT current ratings for:
Understanding of complex diseases likely to improve following the unexpected discovery of the ways Cells Move

A new discovery about how cells move within the organization can provide scientists with crucial information about the mechanisms of diseases such as the spreading of the cancer or constriction of the Airways caused by asthma. Led by researchers from the Harvard School of Public Health (HSPH) and the Institute for bioengineering of Catalonia (IBEC), investigators found that the epithelial cells - the type that form a barrier between the inside and the outside of the body, such as skin cells - move group, powered by forces both of in and from neighbouring cells - to fill the empty spaces that they encounter.

The study appears in Nature Materials advanced online edition.

"We have tried to understand the fundamental relationship between cellular movements collective and collective forces of cell phones, which may occur during the invasion of the cancer cells, for example. But, in so doing, we are fallen on a phenomenon that was totally unexpected, "said lead author Jeffrey Fredberg, Professor of Bioengineering and physiology to the investigator HSPH Department of Environmental Health and co-Minister of HSPH molecular laboratory and integrative cellular dynamics.

Biologists, engineers and physicists at HSPH and IBEC worked together to shed light on the collective cell movement because it plays a key role in functions such as the healing of wounds, organ development and tumor growth. Using a technique called stress monolayer microscopy--which they invented themselves - they have measured the forces affecting a single layer of epithelial cells in motion. They examined cells speed and direction as traction - how certain cells either pull or push themselves and thus force the collective movement.

As they expected, the researchers found that when an obstacle was placed in the path of a layer of advanced cell - in this case, a gel that provided no traction - cells settled around him, closely hugging the sides of the gel as they passed. However, the researchers also found something amazing - cells, in addition to moving forward, continued to collectively back to frost, as if the desire to fill the space empty. Researchers have dubbed this movement "kenotaxis", Greek words "keno" (empty) and "taxi" (arrangement), because it seemed that cells are trying to fill a void.

This new discovery could help researchers to better understand the behaviour of the cell - and evaluate the potential influence that behavior - in a variety of complex diseases, such as cancer, asthma, cardiovascular diseases, developmental anomalies and glaucoma. The findings could also help with regenerative medicine and tissue engineering, which rely on cell migration.

In carcinomas, for example - who represent 90% of all cancers and involve epithelial cells - new information on cell movement could improve understanding of how cancer cells migrate through the body. Research on asthma could also get a boost, because scientists believe the migration of epithelial cells damaged in the lungs are involved in narrowing of the Airways caused by the disease.

"Kenotaxis is a property of the cell collective, not the individual cell," said Jae Hun Kim, first author of the study. "It was amazing to us that the collective cell can organize itself draw systematically in one direction while moving consistently in a quite different direction. ''

Article adapted by Medical News Today press release original. Click on "references" tab above for the source.
Visit our cancer / Oncology section for the latest news on this subject. Other authors HSPH included James Butler, senior lecturer on physiology in the Department of health environmental and investigator co-Minister of the laboratory; and researchers Dhananjay Tambe, Enhua Zhou Chan Young Park, Monirosadat Sadati, Park Jin-Ah, Bomi Gweon and Emil Millet.

Support for the study came from the Spanish Ministry of Science and Innovation (BFU2012-38146 FPU fellowship XS) and the Swiss National Science Foundation (PBEZP2-140047), the National Research Foundation of Korea (2012R1A6A3A03040450), the European Research Council (Grant Agreement 242993) Parker B. Francis (RK Fellowship), American Heart Association (13SDG14320004) and the National Institutes of Health (R01HL102373, R01HL107561).

"Propulsion and navigation within the advanced single layer sheet," Jae Hun Kim, Xavier Serra-Picamal, Dhananjay T. Tambe, Enhua H. Zhou, Chan Young Park, Monirosadat Sadati, Park Jin-Ah, Krishnan Ramaswamy, Bomi Gweon, Emil Millet, James P. Butler, Xavier Trepat, Jeffrey J. Fredberg, Nature of materials, online, June 23, 2013

Harvard School of Public Health

Please use one of the following formats to cite this article in your essay, paper, or report:

MLA

Harvard School of Public Health. "Understanding of complex diseases likely to improve following the unexpected discovery of the ways Cells Move." Medical news today. MediLexicon, international airport, 25 June 2013. Web.
June 25, 2013. APA

Please note: If no author information is provided, the source is cited instead.

?Understanding of complex diseases likely to improve following the unexpected discovery of the ways cells Move?

Please note that we publish your name, but we do not publish your email address. It is only used to notify you when your message is published. We do not use it for other purposes. Please see our privacy policy for more information.

If you write about specific drugs or operations, please are not professional health of the name by name.

All reviews are moderated before they can be included (to stop spam)

Contact our News editors

For any corrections of factual information, or to contact the editors, please use our feedback form.

Please send any new medical or health press releases to:

Note: any medical information published on this website are not intended as a substitute for informed medical advice and you should take any action before consulting professional health care. For more information, please read our terms and conditions.

View the original article here

Gene-Silencing Activity Discovery Could Lead To Treatment For Viral Infections, Cancers And Other Diseases

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Cancer / Oncology;??Genetics
Article Date: 13 May 2013 - 0:00 PDT Current ratings for:
Gene-Silencing Activity Discovery Could Lead To Treatment For Viral Infections, Cancers And Other Diseases

A team led by scientists at The Scripps Research Institute (TSRI) has found how to boost or inhibit a gene-silencing mechanism that normally serves as a major controller of cells' activities. The discovery could lead to a powerful new class of drugs against viral infections, cancers and other diseases.

"Learning to control natural gene silencing processes will allow an entirely new approach to treating human disease," said Ian J. MacRae, assistant professor in TSRI's Department of Integrative Structural and Computational Biology and principal investigator for the study, which appears as the cover story in the May 9, 2013 issue of the journal Molecular Cell.

A Scientific Mystery and Technical Conundrum

The gene-silencer in question is Argonaute 2, a molecular machine in cells that can grab and destroy the RNA transcripts of specific genes, preventing them from being translated into proteins. Argonaute 2 and other Argonaute proteins regulate the influence of about a third of the genes found in humans and other mammals - and thus are among the most important modulators of our cells' day-to-day activities. Argonautes' gene-silencing functions also help cells cope with rogue genetic activity from invading viruses or cancer-promoting DNA mutations.

Yet Argonautes' workings are complex and not yet entirely understood. For example, before it starts a search-and-destroy mission against a specific type of target RNA, an Argonaute 2 protein takes on board a target-recognition device: a short length of "guide RNA," also known as a microRNA (miRNA). The miRNA's sequence is mostly complementary to the target RNA's - a sort of chemical mirror-image - so that it can stick tightly to it.

But how do an Argonaute protein and its miRNA guide, having formed their partnership, manage to part company? It has been a scientific mystery and technical conundrum for researchers, who have found it hard to separate Argonaute proteins from miRNAs in the lab dish.

"That problem led us to look for a way to get Argonautes to unload these miRNAs," said Nabanita De, a postdoctoral fellow in MacRae's laboratory who was first author of the new study.

Matches and Mismatches

In an initial set of experiments, the team demonstrated that when an miRNA hooks up with an Argonaute 2, the pair do remain locked together and functioning for an exceptionally long time: days to weeks, whereas solo miRNA normally is degraded within minutes.

Yet prior studies by other laboratories have hinted at the existence of mechanisms that can hasten the separation of miRNAs from Argonautes. Some viruses, for example, produce decoy target RNAs that virtually nullify the activity of the corresponding miRNAs, seemingly by destabilizing the miRNA-Argonaute pairing. A key feature of these decoy target RNAs is that they make an almost perfect complementary match to the miRNAs - especially at one end of the miRNAs, known as the three-prime or 3' end. In this respect, they match the miRNAs much better than the natural gene transcripts that the miRNAs evolved to target.

De confirmed that decoy RNAs designed to match miRNAs this way can greatly hasten the miRNAs' "unloading" from Argonautes, thus effectively dialing down these miRNAs' normal gene-silencing activities. By contrast, mismatches at the 3' end delayed unloading, enhancing the gene-silencing activity.

Why do these matches and mismatches have such effects on the miRNA-Argonaute pairing? The mechanisms aren't obvious. But De noted that mismatches at the opposite end of miRNAs - the 5' end - have the opposite effect. "Targets with 5'-end mismatches are actually better at unloading miRNAs from Argonaute," she said.

"The next thing we're trying to figure out is how all that works," said MacRae. "We have some guesses but no clear answer."

In a study reported last year, MacRae's laboratory used X-ray crystallography to determine the first high-resolution atomic structure of an Argonaute 2-miRNA complex. Now the team is working on a structural study of the complex as it grabs a target RNA. "When we can see the structural details of that interaction, then I think we'll have a much better handle on this loading and unloading process," said MacRae.

Many Potential Applications

Scientists already have begun developing gene-silencing drugs that work like miRNAs; they are taken up by Argonaute proteins as guide RNAs and lead to the silencing of targeted gene transcripts. Pharmaceutical companies also are developing drugs that bind directly to miRNAs to inhibit their activity. The findings here suggest a new and, in principle, more powerful class of miRNA inhibitors/enhancers, aimed at destabilizing or stabilizing the miRNA-Argonaute complex.

"I can think of many applications for these," said MacRae. "One of the most obvious would be against hepatitis C virus, which requires a certain miRNA in liver cells for efficient replication; an RNA-based drug that speeds up the unloading of this virus-enhancing miRNA would be a powerful approach for shutting down the virus."

A better understanding of the miRNA loading and unloading process also should lead to better miRNA-type drugs, he added.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our infectious diseases / bacteria / viruses section for the latest news on this subject. Other contributors to the study, "Highly Complementary Target RNAs Promote Release of Guide RNAs from Human Argonaute 2," were Lisa Young, Nicole-Claudia Meisner and David V. Morrissey of the Novartis Institutes for Biomedical Research, and Pick-Wei Lau of the MacRae laboratory at TSRI.
The study was funded by the National Institutes for Health (grant R01 GM086701).
Scripps Research Institute Please use one of the following formats to cite this article in your essay, paper or report:

MLA

Institute, Scripps Research. "Gene-Silencing Activity Discovery Could Lead To Treatment For Viral Infections, Cancers And Other Diseases." Medical News Today. MediLexicon, Intl., 13 May. 2013. Web.
13 May. 2013. APA

Please note: If no author information is provided, the source is cited instead.

'Gene-Silencing Activity Discovery Could Lead To Treatment For Viral Infections, Cancers And Other Diseases'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam)

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here