Scientists Capture Single Cancer Molecules At Work

Main Category: Cancer / Oncology
Article Date: 12 Dec 2011 - 0:00 PST

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Researchers have revealed how a molecule called telomerase contributes to the control of the integrity of our genetic code, and when it is involved in the deregulation of the code, its important role in the development of cancer. The University of Montreal scientists involved explain how they were able to achieve their discovery by using cutting edge microscopy techniques to visualize telomerase molecules in real time in living cells in Molecular Cell on December 9, 2011.

"Each time our cells divide, they need to completely copy the genomic DNA that encodes our genes, but the genome gets shorter each time until the cell stops dividing," said Dr. Pascal Chartrand, a biochemistry professor at the University of Montreal and a senior author of the study. "However, the telomerase molecules can add bits of DNA called telomeres to the ends of our genome. Telomeres prevent the genome from deteriorating or joining up with other pieces of DNA, allowing cells to divide indefinitely and become cancerous. Normally, the telomerase gene is not active, but how it is controlled is poorly understood. One difficulty has been that we need to see exactly what individual telomerase molecules are doing on our genome and when." Franck Gallardo, the study's lead author, added that the team was able to apply techniques from other work that the team was doing in their lab. "We could in fact visualize what individual telomerases were doing in cells," he said.

In collaboration with Nancy Laterreur and Dr. Raymund Wellinger of the Université de Sherbrooke, Dr. Gallardo was able to tag telomerase with fluorescent proteins, which allowed them to visualize telomerase in single living cells. With this technological breakthrough, they observed that, contrary to previous theories, several molecules of telomerase cluster on only a few telomeres, and elongate the telomeres at each cell cycle. Moreover, they identified regulatory factors that restrain the activity of telomerase within a narrow time window when the cell is dividing. This new technology opens up the possibility of studying the activity of a key factor in the development of cancer at the molecular level within its cellular environment.

Professor Chartrand's research is supported by Canadian Institutes of Health Research (www.cihr-irsc.gc.ca) and by the Fonds de la recherche en Santé du Québec (www.frsq.gouv.qc.ca).

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 study, "Live cell imaging of telomerase RNA dynamics reveals cell cycle-dependent clustering of telomerase at elongating telomeres", published in Molecular Cell, was authored by Franck Gallardo, Nancy Laterreur, Emilio Cusanelli, Faissal Ouenzar, Emmanuelle Querido, Raymund J Wellinger and Pascal Chartrand.

Dr. Chartrand's research

University of Montreal

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Changing The Locks: HIV Discovery Could Allow Scientists To Block Virus's Entry Into Cell Nucleus

Main Category: HIV / AIDS
Article Date: 11 Dec 2011 - 0:00 PST

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Scientists have found the 'key' that HIV uses to enter our cells' nuclei, allowing it to disable the immune system and cause AIDS The finding, published today in the open access journal PLoS Pathogens, provides a potential new target for anti-AIDS drugs that could be more effective against drug-resistant strains of the virus.

HIV is transmitted through bodily fluids, primarily infected blood or semen. Once inside the bloodstream, the virus infects key components of the immune system including cells known as macrophages. It works its way into the nucleus of the macrophages, where it integrates itself into the cell's DNA, allowing it to replicate and spread throughout the body.

To access the DNA, the HIV must pass through the Nuclear Pore Complex, a gateway into the nucleus. Until now, the mechanism that allows the virus to pass through this gateway was unknown. Now, a team of scientists from UCL (University College London), the University of Pennsylvania School of Medicine and the Laboratory of Molecular Biology in Cambridge, has identified a vital component of this mechanism. A part of the HIV virus called the capsid protein, acting like a key, binds to Nup358, a protein on the nuclear pore complex, unlocking the gateway and granting the virus access to the DNA.

Professor Greg Towers, a Wellcome Trust Senior Research Fellow at UCL, who led the research, says: "It's thirty years since the first cases of AIDS were reported and whilst great progress has been made in developing and improving antiretroviral drugs for treating HIV infection, the virus often develops resistance against these drugs making it very difficult to treat. It's very important that we stay one step ahead with new therapeutic strategies.

"In our research, we have found the 'lock and key' that allow HIV to enter a cell's nucleus. Once inside, the virus can begin to replicate itself, spreading almost unchecked throughout the body. If we were able to block this entry with a drug - in effect, to change the locks - then we could stop this spread."

Targeting proteins in the host, rather than in the virus itself, has added benefits, explains first author Dr Torsten Schaller.

"Almost all HIV treatments target the virus itself," he explains. "We know that HIV can easily evolve and change, which means that the virus can become immune to the effects of the drugs, rendering them ineffective. But if we can develop drugs which target proteins in the infected person's body, the virus will struggle to evolve to get around this."

According to the World Health Organization, 33.3 million people were living with HIV in 2009, of which 2.6 million were newly infected. Without treatment, the virus causes potentially fatal damage to the immune system, leading to opportune infections. Deaths from AIDS-related illnesses are the third most common cause of death in low-income countries, killing around 1.8 million people a year worldwide.

The research was funded by the Wellcome Trust, the National Institute of Health Research and the Medical Research Council in the UK, and the National Institutes of Health, the University of Pennsylvania Center for AIDS Research, and the Pennsylvania Department of Health in the US.

Professor Danny Altmann, Head of Pathogens, Immunology and Population Health at the Wellcome Trust, said: "This is exciting work into somewhat uncharted territory. Professor Towers and colleagues have taken a big step towards modelling how HIV enters and integrates itself into the cell's DNA and then uses it to replicate. It offers the prospect of novel ways to try and combat HIV infection."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Scientists Show How BRCA1 Cancer Gene Mutations Harm Breast Cells

Main Category: Breast Cancer
Also Included In: Genetics
Article Date: 09 Dec 2011 - 2:00 PST

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Working with human breast cells, researchers at the Johns Hopkins Kimmel Cancer Center have shown how the inactivation of a single copy of the breast cancer gene BRCA1 leaves breast cells vulnerable to cancer by reducing their ability to repair DNA damage, causing genetic instability. An inherited mutation in BRCA1 is the leading risk factor for hereditary breast cancer, prompting preventive mastectomies or close monitoring. The new findings may aid development of drugs to prevent hereditary breast cancer and tools to identify women who benefit most from prophylactic treatments.

Precisely how BRCA1 inactivation raises cancer risk has remained something of a puzzle. BRCA1 is considered a "tumor suppressor" gene, and typically the loss of one copy of such genes is not enough to cause cancer. That's because humans inherit two copies of each gene (one from each parent), and the second copy works well enough to keep cells healthy just as a car can safely stop after losing the front brakes since the rear brakes are still intact. Cancer apparently develops in such cases only after the second copy is inactivated in a cell, perhaps by some random mutation during cell division, resulting in the "second hit" causing uncontrolled cell growth as if the cell lost its "brakes."

Mouse models of BRCA-related cancers have shown that "hits" to genes such as TP53 occur before the second "hit" to the remaining functional copy of BRCA. "In theory, this process would take a long time, and BRCA-related breast cancers occur at an early age," according to Ben Ho Park, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

For the study, reported in the Proceedings of the National Academy of Sciences Oct. 25, Park and his team at Johns Hopkins took advantage of new technology to introduce a single copy of a typical BRCA1 mutation into normal breast cells.

The leading hypothesis has been that the original inactivation of a single copy of BRCA1 causes further DNA mutations to accumulate more quickly than normal a condition called "genomic instability." The protein coded by BRCA1 is involved in repairing major DNA breaks, so it would make sense that its inactivation could weaken a cell's resistance to DNA mutations, says Park.

But the consequence of losing a single copy of BRCA1 was not easy to model or study, he adds. Previous efforts to create mice with single-copy BRCA1 mutations had uncertain results because the mice failed to show the pattern of human cancers. Researchers also have found it difficult to create human cell lines in which the only flaw is a single mutated copy of BRCA1.

To test the idea, Park's team first selected cell lines derived from non-cancerous human breast epithelial cells where BRCA1 breast cancers originate. They then used an advanced gene-targeting technique to create new cell lines that have a typical cancer-linked BRCA1 mutation in only one copy of the gene.

Park's team then ran tests on the two cell types the ones that had the BRCA1 mutation, and the original cells that had two healthy copies of BRCA1 and compared their DNA repair activity. They were able to show that cells with BRCA1 mutations were less efficient at conducting the type of DNA repair known to involve the BRCA1 protein. The BRCA1-mutated cells were more likely to die when exposed to a DNA-damaging chemotherapy drug or radiation. BRCA1-mutated cells allowed to divide for several weeks also were more likely to lose other genes, including genes often mutated in breast tumors. Tests on non-cancerous breast cells taken from women with BRCA1 mutations showed similar genetic losses.

"What this shows is that having only a single working copy of BRCA1 really does bring about changes in a cell that would be expected to give rise to cancer," Park says.

Park plans additional experiments on their new cell models of BRCA1-mutations. "We hope to use this new system to introduce other known BRCA1 mutations, to get a better idea of the relative cancer risk each individual mutation represents, because right now there are few good ways to do that," he says. "In the future, we hope to further define risk so that family members with one type of BRCA1 mutation may be advised to get preventive treatment or surgery, and those with other BRCA1 mutations could rely on careful screening."

The new cell models also may be useful in determining the susceptibility of various BRCA1 mutations to drugs, he adds. Anti-cancer drugs known as PARP inhibitors are currently in clinical trials against tumors with BRCA1-mutations.

Women born with a mutated copy of BRCA1 have been shown to have lifetime risks of breast cancer between 50 and 90 percent, a wide range. They also have high, but variable, risks of ovarian and other cancers.

Article adapted by Medical News Today from original press release. Source: Johns Hopkins Medicine
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Scientists Identify Strategies To Conquer Lifestyle And Genetic Factors Related To Chronic Diseases

Main Category: Genetics
Also Included In: Allergy;  Immune System / Vaccines
Article Date: 08 Dec 2011 - 2:00 PST

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A dramatic increase in the incidence of chronic inflammatory diseases such as asthma, allergy, and irritable bowel syndrome, has led to concern about how modern lifestyles may trigger physiological defense mechanisms. Now, in the context of a foresight study under the auspices of the European Science Foundation (ESF), a group of scientists has examined the challenges associated with chronic inflammatory diseases, and described 10 key areas with the highest priority for research. Their recommendations are published in a supplement to The Journal of Allergy and Clinical Immunology (JACI), the official journal of the American Academy of Allergy, Asthma & Immunology (AAAAI).

"Many transmissible diseases have been effectively eradicated over the last half century, yet there has been a marked increase in the incidence of chronic inflammatory diseases," says committee chair Harald Renz, MD, of the Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Phillips University, Marburg, Germany. Strategies are urgently needed to determine the causes of these chronic diseases and identify targets for therapy and prevention."

Factors responsible for the development of chronic inflammatory diseases are not easily determined. While epidemiological evidence clearly points to an environmental influence, not all individuals in these environments develop disease. Susceptibility to chronic inflammatory disease has a clear genetic component, but genetics may not be the only determining factor. Prenatal exposures can influence later susceptibility to disease. After birth, factors such as breastfeeding and exposure to microorganisms appear to further influence the likelihood of developing diseases such as asthma and allergy.

Dr. Renz and his colleagues on the Scientific Committee of the ESF Forward Look on Gene-Environment Interaction in Chronic Disease (GENESIS) identified the following 10 key recommendations as having the highest priority for research into chronic inflammatory diseases:

1. Research should distinguish between therapy and prevention.

2. Large prospective cohort studies including deep phenotyping should be made a priority.

3. Research should focus on the question of tolerance.

4. A global (international) approach should be taken to understanding chronic inflammatory disease.

5. Effective interdisciplinary research strategies must be established.

6. New tools and experimental models must be developed.

7. Protocols for data collection, handling, and storage need to be harmonized.

8. Substantial investment must be made in infrastructure, personnel, and development of research tools.

9. Dedicated funding must be provided for interdisciplinary research.

10. Effective public-private partnerships must be developed to ensure free exchange of information.

Furthermore, the committee pointed to a series of key strategic research targets for which significant progress in the management of chronic diseases may be achieved.

Therapy and Prevention. Given the complexity of chronic inflammatory diseases, therapies must be based on deep environmental, clinical and biological phenotyping of patients. Without deep phenotyping, it is impossible to determine whether a potential therapy is clinically ineffective or simply inappropriately targeted. The committee calls for the identification of novel biological markers to enhance patient stratification, and for investments in bioinformatics and systems biology to realize the full potential of omics data.

For prevention, key issues include the selection of appropriate populations and the long-term tolerability of putative long-term protective agents. The results of clinical studies of probiotics as infant food supplements to prevent allergic disease have been mixed. The committee recommends that the term probiotic be employed with caution, and that further research be done to understand the function of gut microbes in health and disease.

Large Cohort Studies. The committee calls for large cohort studies, initiated prior to birth, to fully take into account the impact of how intrinsic and extrinsic factors determine the probability that an individual will be healthy or develop a chronic disease, given the right environmental stimuli. Such studies would analyze biological data including genomic, clinical, and environmental factors, and also psychosocial factors such as stress. It will be important to ensure international collaboration and coverage of populations with different lifestyles and environmental exposures.

Partnerships. The shifting global pattern of chronic disease to developing nations offers an opportunity to identify key factors that confer both risk and protection. The committee recommends that research projects be established in regions with low or developing risk of chronic inflammatory disease, and the establishment of parallel birth cohorts in low- and high-risk regions. Cross-disciplinary partnerships will be essential as well, extending beyond traditional disciplines such as epidemiology and microbiology to mathematics, virology, and ecology. Finally, effective private-public partnerships, with more fluid exchanges of information between academia and industry, will be a key driving force for future research.

Research Tools, Data Generation and Management, and Infrastructure and Personnel. New research strategies that consider the diversity of the microbiome in the choice of experimental models and the potential reproducibility of results will be needed. Because of the complexity introduced by the microbiome, substantial investment will be required to develop the bioinformatics and systems biology approaches required to analyze the datasets generated. An electronic infrastructure to support integrated approaches and open collaboration will be necessary. Funding should be made by panels in which no specific discipline is over-represented to support unbiased approaches. And, a new generation of biological and medical scientists will need to be ready to exploit rapid developments in information technology. They will need to use insights from a range of scientific disciplines as well as fields as diverse as finance and engineering. The committee suggests the creation of international graduate schools to provide specific training in interdisciplinary research.

In the foreword accompanying the supplement, Lars V. Kristiansen, PhD, Science Officer, European Science Foundation, European Medical Research Councils, Strasbourg, France, and colleagues comment, "The socioeconomic costs of chronic diseases are staggering and ever increasing. There is an urgent need to prioritize resources and identify the most efficient scientific and societal initiatives to be adopted. National collaboration within the European region represents the most efficient manner in which strategies for amelioration of chronic inflammatory diseases in the western world may be achieved."

Article adapted by Medical News Today from original press release. Source: Elsevier
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