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.

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New Study Reveals Important Mechanism For Tumorigenesis

Main Category: Cancer / Oncology
Article Date: 08 May 2013 - 1:00 PDT Current ratings for:
New Study Reveals Important Mechanism For Tumorigenesis

Cancer is a complex disease, in which cells undergo a series of alterations, including changes in their architecture; an increase in their ability to divide, to survive and to invade new tissues or metastasis. A category of genes, called oncogenes, is critical during cancer progression, as they codify proteins whose activity favours the development of cancer. One of these molecules, Src, is implicated in a large number of human cancers. However, it is still not clear how healthy cells constrain its activity not to become tumorous. In the latest issue of the journal Oncogene*, Florence Janody and her team at the Instituto Gulbenkian de Ciencia (IGC, Portugal), identified a novel mechanism by which the activity of Src is limited by the cell's skeleton (named cytoskeleton) limiting the development of tumours.

Using the fruit fly, Drosophila melanogaster, as a model, Florence Janody and her team were able to stop the tumour development induced by the high activity of Src through the genetic manipulation of the cytoskeleton in fly tissues. A major component of the cytoskeleton, the actin protein, form cables that crisscross the cell, creating a network, where molecules can move, inside the cell. These cables are constantly being elongated and shortened at their ends in a process tuned by molecules called actin-Capping Proteins. Florence Janody’s team showed that the development of tumours is stopped in the presence of high levels of the actin Capping Protein. This "tuner" restrains the activity of proteins that are usually activated by high levels of Src. Although the precise molecular mechanism is still unknown, the hypothesis raised by these scientists is that the "tuner" creates a tension in the cables of the cytoskeleton that impedes the action of these proteins. Conversely, the activity of Src is higher when the levels of the actin Capping Protein are lower, as the proteins activated by Src are able to escape the blocking effect of the network and act in the cell, resulting in the development of tumours. Thus, when the cytoskeleton network is not tightly regulated, the activity of oncogenes such as Src is not trapped and tumour development is observed.

Florence Janody says: "The cytoskeleton works as a "barbwire" network. The winner of the competition between molecules of the "barbwire" network and the Src oncogene, which fights against it, will determine whether the cell will stay healthy or become a cancer cell.

Beatriz Garcia Fernandez and Barbara Jezowska, first authors of this work added: "Our work suggests that the appearance of mutations in molecules that regulate the skeleton may play a significant role in inducing cancer development during the early stages of the disease by releasing the activity of oncogenes."

Src was the first oncogene described in the 1950s as capable to induce cancer. This discovery was awarded with the Nobel Prize in Physiology and Medicine in 1989.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. This study was carried out at the IGC and was funded by Fundacao para a Ciencia e a Tecnologia (Portugal).

*Garcia Fernandez, B., Jezowska, B., and Janody, F. (2013) Drosophila actin-Capping Protein limits JNK activation by the Src proto-oncogene, Oncogene, May 6, doi:10.1038/onc.2013.155

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Process Of Metastasis Explained By 'Chase And Run' Cell Movement Mechanism

Main Category: Cancer / Oncology
Article Date: 18 Jun 2013 - 1:00 PDT Current ratings for:
Process Of Metastasis Explained By 'Chase And Run' Cell Movement Mechanism

A mechanism that cells use to group together and move around the body - called 'chase and run' - has been described for the first time by scientists at UCL.

Published in Nature Cell Biology, the new study focuses on the process that occurs when cancer cells interact with healthy cells in order to migrate around the body during metastasis. Scientists know that cancer cells recruit healthy cells and use them to travel long distances, but how this process takes place and how it could be controlled to design new therapies against cancer remains unknown.

Now, using embryonic cells called 'neural crest cells' (which are similar to cancer cells in terms of their invasive behaviour) and placode cells which are the precursors for cranial nerves (the equivalent to healthy cells) researchers at UCL have started to unravel this process.

They have found that when neural crest cells are put next to placode cells they undergo a dramatic transformation and start 'chasing' the placode cells. At the same time placode cells exhibite 'escape' behaviour when contacted by neural crest cells. The chasing behavior depends on the production of small chemical molecules by the placode cells that attracts neural crest cells toward them.

The authors of the study are confident that the process whereby cancer cells attached to healthy cells in order to migrate around the body is comparable. Healthy cells of the body try to escape from tumor cells, but are followed by malignant cells because the healthy cells produce an attractant for the cancer cells.

Dr Roberto Mayor, UCL Department of Cell and Developmental Biology and lead author of the research, said, "We use the analogy of the donkey and the carrot to explain this behaviour: the donkey follows the carrot, but the carrot moves away when approached by the donkey. Similarly the neural crest cells follow the placode cells, but placode cells move away when touched by neural crest cells."

"The findings suggest an alternative way in which cancer treatments might work in the future if therapies can be targeted at the process of interaction between malignant and healthy cells to stop cancer cells from spreading and causing secondary tumours."

"Most cancer deaths are not due to the formation of the primary tumor, instead people die from secondary tumors originating from the first malignant cells, which are able to travel and colonize vital organs of the body such as the lungs or the brain."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. The work was funded by the Medical Research Council and the Wellcome Trust.
'Chase-and-run between adjacent cell populations promotes directional collective migration' is published in the journal Nature Cell Biology.
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Previously Unknown Surveillance Mechanism Used By Cells To Monitor Oxidatively Damaged DNA

Main Category: Genetics
Also Included In: Alzheimer's / Dementia;??Cancer / Oncology;??Parkinson's Disease
Article Date: 18 Jun 2013 - 1:00 PDT Current ratings for:
Previously Unknown Surveillance Mechanism Used By Cells To Monitor Oxidatively Damaged DNA

In current health lore, antioxidants are all the rage, as "everybody knows" that reducing the amount of "reactive oxygen species" -- cell-damaging molecules that are byproducts of cellular metabolism -- is critical to staying healthy. What everyone doesn't know is that our bodies already have a complex set of processes built into our cells that handle these harmful byproducts of living and repair the damage they cause.

For example, few of us realize that, while our cells' DNA is constantly being damaged by reactive oxygen species (as well as by other forces), there are also complex mechanisms that constantly assess that damage and make repairs to our fragile genetic material at least 10,000 times a day in every cell in our bodies. The vital biochemical processes by which this constant DNA repair takes place are still only partially understood because of their complexity, speed, and the difficulty of studying complex interactions within living cells. Moreover, it remains unknown how cells sense the oxidatively damaged DNA in the first place.

In an article published in the Proceedings of the National Academy of Sciences (PNAS) a research team from University of North Carolina at Charlotte announced that they had uncovered a previously unknown surveillance mechanism, known as a DNA damage checkpoint, used by cells to monitor oxidatively damaged DNA. The finding, first-authored by UNC Charlotte biology graduate student Jeremy Willis and undergraduate honors student Yogin Patel, was also co-authored by undergraduate honors student Barry L. Lentz and assistant professor of biology Shan Yan.

"DNA damage is the underlying pathology in many major human diseases, including cancers and neurodegenerative disorders such as Alzheimer's and Parkinson's, so arriving at a full understanding of the sophisticated mechanisms that cells usually employ to avoid such disastrous outcomes is important," Yan noted.

Two biochemical pathways, known as ATM-Chk2 and ATR-Chk1, govern the cell's response and repair of double-strand DNA breaks and other types of DNA damage or replication stress respectively. The molecular mechanisms underlying the ATR-Chk1 checkpoint activation include the uncoupling of DNA helicase and polymerase activities and DNA end resection of double-strand breaks.

"The significance of what we have found is that there is a third, previously unknown trigger for ATR-Chk1 checkpoint pathway, and this novel mechanism is discovered in the context of oxidative stress," Yan said.

In particular, Yan's team discovered that under conditions of oxidative stress (in the presence of hydrogen peroxide) a base excision repair protein known as APE2 plays unexpected roles in the checkpoint response: single-strand DNA generation and Chk1 association. The protein was previously known to be involved in the DNA repair of oxidative damage, but not to extent revealed in the study's findings. The distinct role of APE2 in the single-strand DNA generation in 3' to 5' direction is referred to as single-strand break end resection ("SSB end resection") by the authors.

The study involved experiments performed with Xenopus laves (the African clawed frog, a species commonly used as a lab animal) egg extracts - an experimental system that Yan's lab has developed for studying DNA repair and checkpoint mechanisms in a cell-free conditions. Xenopus is useful because it is a vertebrate (and thus quite similar to humans in cell biology), and its egg cells can be easily produced and manipulated.

Yan is hopeful that this research will open new avenues to pharmacological strategies in drug development for cancer and neurodegenerative diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject. The article appeared in the June 10, 2013 print edition of PNAS: http://www.pnas.org/content/early/2013/06/06/1301445110.abstract.
The Yan laboratory at UNC Charlotte is funded in part by the University of North Carolina at Charlotte and a National Institute of General Medical Sciences/National Institutes of Health grant, number R15GM101571.
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