Multiple myeloma: link to gene involved in aging

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Main Category: Genetics
Also Included In: Cancer / Oncology;  Blood / Hematology
Article Date: 19 Aug 2013 - 8:00 PDT Current ratings for:
Multiple myeloma: link to gene involved in aging

Researchers say that a gene responsible for helping to control the aging process by regulating a "cell's internal clock" may be linked to a type of blood cancer.

Scientists from The Institute of Cancer Research in the UK found a genetic variant called TERC among four new variants that they linked to multiple myeloma - a form of cancer that affects immune cells produced in the bone marrow for circulation in the blood. Their findings are published in the journal Nature Genetics.

The researchers say that this latest discovery takes the number of total genetic variants linked to myeloma to seven, and may help lead to the discovery of genetic causes of the disease.

Myeloma is a relatively uncommon cancer according to the American Cancer Society statistics, with a 1 in 149 risk of developing the disease in the US.

For the study, the research team analyzed the genetic make-up of 4,692 patients who had myeloma, and compared this with DNA of 10,990 people who did not have the blood cancer.

The scientists say that in a previous study they conducted, three genetic variants were discovered in DNA, which was found to increase the risk of myeloma.

The new batch of variants in this most recent study were discovered by combining these samples with other samples collected by researchers in Germany. The researchers add that this produced more data and more statistical accuracy.

From this, the genetic variant TERC was discovered. It works, the scientists explain, by regulating the length of telomere "caps" (protective caps) on the ends of DNA. Over time, these caps erode in healthy cells, causing tissues to age.

But the researchers say that some cancer cells appear to be ignoring the aging trigger and continue to divide. They add that if the link between TERC and myeloma is confirmed, this could lead to new treatments of the blood cancer.

Richard Houlston, professor of molecular and population genetics at The Institute of Cancer Research (ICR), explains: "Our study has taken an important step forward in understanding the genetics of myeloma, and suggested an intriguing potential link with a gene that acts as a cell's internal timer."

Prof. Houlston adds:

"We know cancer often seems to ignore the usual controls over aging and cell death, and it will be fascinating to explore whether in blood cancers, that is a result of a direct genetic link.

Eventually, understanding the complex genetics of blood cancers should allow us to assess a person's risk or identify new avenues for treatment."

Professor Chris Bunce, research director at Leukemia & Lymphoma Research, says this research offers more evidence that the risk of myeloma can be inherited.

"By showing how these specific genes influence the cancer's development, this research could potentially lead to the development of targeted myeloma drugs in the future," adds Prof. Bunce.

"In addition we know that a common condition called MGUS predisposes to the development of myeloma. The identification of additional genetic risk factors in these patients could revolutionize their future management and prospects."

Written by Honor Whiteman

Reference: 'Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk,' Daniel Chubb, Niels Weinhold, Peter Broderick. Letter to Nature Genetics published online 18 August 2013 (doi:10.1038/ng.2733).
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Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology;  Diabetes
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Deciphering the body's complex molecular pathways that lead to disease when they malfunction is highly challenging. Researchers at Sanford-Burnham Medical Research Institute now have a more complete picture of one particular pathway that can lead to cancer and diabetes. In the study published by Molecular Cell, the scientists uncovered how a protein called p62 has a cascade affect in regulating cell growth in response to the presence of nutrients such as amino acids and glucose. Disrupting this chain may offer a new approach to treating disease.

The protein p62 interacts with another protein called TRAF6 to activate a protein complex called mTORC1. In fact, researchers have found that mTORC1, also known as mammalian target of rapamycin complex 1, is highly activated in cancer cells. The pathway that controls mTORC1 activation is also important for metabolic homeostasis (i.e., stability). When the pathway malfunctions, metabolic disorders such as diabetes can result and tumors can progress.

About a year ago, Maria Diaz-Meco, Ph.D., Jorge Moscat, Ph.D., and their colleagues had identified that p62 is an important player in this complex pathway. But they didn't know how. Their new study shows that p62 activates mTORC1 through TRAF6.

"The mTORC1 pathway is a major complex important not only for cancer but also for metabolic homeostasis," said Diaz-Meco. "For that reason, it's very important to unravel the mechanism that controls how mTORC1 responds to the different signals."

"mTORC1 responds to many growth signals," she added, "but the specific mechanisms that channel the activation of mTORC1 by nutrients such as amino acids and glucose are still not completely understood. Our goal was to discern the specific mechanisms that regulate this important pathway."

The researchers found that TRAF6 plays a role in activating mTORC1 by molecularly modifying it in a process called ubiquitination. TRAF6, meanwhile, itself becomes activated in the presence of amino acids. "When you have a diet high in meat, the concentration of amino acids in your blood increases, and that's a way to activate this pathway," Moscat said. This can have tremendous implications not only for diabetes, but also for cancer-cell proliferation, which needs a constant supply of nutrients to grow.

More work is needed to fully understand the pathway, but the researchers next plan is to find ways to disrupt the interaction between p62 and TRAF6, with the ultimate goal of inactivating mTORC1 and therefore controlling cancer progression. "Because mTORC1 is a highly important protein that regulates growth, therapies aimed at blocking mTORC1 activation may offer a new approach to treating disease," Diaz-Meco said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

This work was supported by grants from the U.S. National Institutes of Health (grants R01CA132847, R01AI072581, R01DK088107, R01CA134530M).

Juan F. Linares, Sanford-Burnham; Angeles Duran, Sanford-Burnham; Tomoko Yajima, Sanford-Burnham; Manolis Pasparakis, Institute for Genetics, University of Cologne (Germany); Jorge Moscat, Sanford-Burnham; and Maria T. Diaz-Meco, Sanford-Burnham.

Sanford-Burnham Medical Research Institute

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Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology;  Diabetes
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth

Deciphering the body's complex molecular pathways that lead to disease when they malfunction is highly challenging. Researchers at Sanford-Burnham Medical Research Institute now have a more complete picture of one particular pathway that can lead to cancer and diabetes. In the study published by Molecular Cell, the scientists uncovered how a protein called p62 has a cascade affect in regulating cell growth in response to the presence of nutrients such as amino acids and glucose. Disrupting this chain may offer a new approach to treating disease.

The protein p62 interacts with another protein called TRAF6 to activate a protein complex called mTORC1. In fact, researchers have found that mTORC1, also known as mammalian target of rapamycin complex 1, is highly activated in cancer cells. The pathway that controls mTORC1 activation is also important for metabolic homeostasis (i.e., stability). When the pathway malfunctions, metabolic disorders such as diabetes can result and tumors can progress.

About a year ago, Maria Diaz-Meco, Ph.D., Jorge Moscat, Ph.D., and their colleagues had identified that p62 is an important player in this complex pathway. But they didn't know how. Their new study shows that p62 activates mTORC1 through TRAF6.

"The mTORC1 pathway is a major complex important not only for cancer but also for metabolic homeostasis," said Diaz-Meco. "For that reason, it's very important to unravel the mechanism that controls how mTORC1 responds to the different signals."

"mTORC1 responds to many growth signals," she added, "but the specific mechanisms that channel the activation of mTORC1 by nutrients such as amino acids and glucose are still not completely understood. Our goal was to discern the specific mechanisms that regulate this important pathway."

The researchers found that TRAF6 plays a role in activating mTORC1 by molecularly modifying it in a process called ubiquitination. TRAF6, meanwhile, itself becomes activated in the presence of amino acids. "When you have a diet high in meat, the concentration of amino acids in your blood increases, and that's a way to activate this pathway," Moscat said. This can have tremendous implications not only for diabetes, but also for cancer-cell proliferation, which needs a constant supply of nutrients to grow.

More work is needed to fully understand the pathway, but the researchers next plan is to find ways to disrupt the interaction between p62 and TRAF6, with the ultimate goal of inactivating mTORC1 and therefore controlling cancer progression. "Because mTORC1 is a highly important protein that regulates growth, therapies aimed at blocking mTORC1 activation may offer a new approach to treating disease," Diaz-Meco said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.

This work was supported by grants from the U.S. National Institutes of Health (grants R01CA132847, R01AI072581, R01DK088107, R01CA134530M).

Juan F. Linares, Sanford-Burnham; Angeles Duran, Sanford-Burnham; Tomoko Yajima, Sanford-Burnham; Manolis Pasparakis, Institute for Genetics, University of Cologne (Germany); Jorge Moscat, Sanford-Burnham; and Maria T. Diaz-Meco, Sanford-Burnham.

Sanford-Burnham Medical Research Institute

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Sanford-Burnham Medical Research Institute. (2013, August 5). "Researchers map a new metabolic pathway that controls mTORC1 activation which is involved in cell growth." Medical News Today. Retrieved from
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Study suggests role for adenosine in molecular processes involved in epilepsy

Main Category: Epilepsy
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
Study suggests role for adenosine in molecular processes involved in epilepsy

Silk has walked straight off the runway and into the lab. According to a new study published in the Journal of Clinical Investigation, silk implants placed in the brain of laboratory animals and designed to release a specific chemical, adenosine, may help stop the progression of epilepsy. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB), which are part of the National Institutes of Health.

The epilepsies are a group of neurological disorders associated with recurring seizures that tend to become more frequent and severe over time. Adenosine decreases neuronal excitability and helps stop seizures. Earlier studies have suggested abnormally low levels of adenosine may be linked to epilepsy.

Rebecca L. Williams-Karnesky, Ph.D. and her colleagues from Legacy Research Institute, Portland, Ore., Oregon Health and Sciences University (OHSU), Portland, and Tufts University, Boston, looked at long-term effects of an adenosine-releasing silk-implant therapy in rats and examined the role of adenosine in causing epigenetic changes that may be associated with the development of epilepsy.

The investigators argue that adenosine's beneficial effects are due to epigenetic modifications (chemical reactions that change the way genes are turned on or off without altering the DNA code, the letters that make up our genetic background). Specifically, these changes happen when a molecule known as a methyl group blocks a portion of DNA, affecting which genes are accessible and can be turned on. If methyl groups have been taken away (demethylated), genes are more likely to turn on.

The results reported in the paper provided evidence that changing adenosine levels affects DNA methylation in the brain. Specifically, greater amounts of adenosine were associated with lower levels of DNA methylation. The investigators also demonstrate that rats induced to develop epilepsy have higher levels of methylated DNA. Of particular note, epileptic rat brains that had received the adenosine-releasing silk implants exhibited DNA methylation levels close to brains of normal rats and this significantly lessened the worsening of the epilepsy over time.

"We know that there are mutations that are associated with epilepsy. However, there are few people such as Dr. Detlev Boison who are doing this type of work, focusing not just on genetic mutations but how the genes are regulated," said Vicky Whittemore, Ph.D., program director at NINDS.

One mechanism involved in a specific type of epilepsy is an increase in mossy fiber sprouting - the formation of new excitatory circuits in the part of the brain where seizures commonly originate. At the end of the experiment, animals that had been treated with the adenosine-releasing silk implant showed less sprouting than animals that were not given the drug. "Based on our findings that 10 days of adenosine delivery prevented the sprouting of mossy fibers for at least three months in rats, we predict that the benefits of our adenosine therapy may extend even longer. However, this assumption needs to be validated in long-term experiments that go beyond three months," said Dr. Boison, senior author of the paper from Legacy Research Institute and OHSU.

The rats did not receive the implants until they had experienced a number of seizures. The researchers noted that many studies investigating anti-epileptic drugs often test the treatments too early. "If the therapy interferes with the trigger for epilepsy development then the trigger is weakened and subsequent epilepsy is less severe. However, this is not necessarily indicative of a stop in the progression of the disease," said Dr. Boison. They found that the adenosine-releasing silk did not completely abolish seizures in their animal model but reduced them four-fold.

"To avoid interference with the epilepsy-triggering mechanisms, we waited until all animals developed an early stage of epilepsy. In this model, the disease is life-long: seizures become more frequent and worsen with time. Therefore, we challenged ourselves to attempt treatment at a stage where epilepsy had already been established," Dr. Boison continued.

The findings show that the implants are safe to use in rats and suggest that they may one day be used in the clinic. "Adenosine-releasing silk is a biodegradable implant. The release of adenosine occurs for 10 days and then the silk will completely dissolve. This is an ideal set-up for a transient preventative treatment," said Dr. Boison. "Clinical applications could be the prevention of epilepsy following head trauma or the prevention of seizures that often - in about 50 percent of patients - follow conventional epilepsy surgery. In this case, adenosine-releasing silk might be placed into the resection cavity in order to prevent future seizures."

However, before the silk implants are ready for their close-up, future studies will need to determine their optimal use and safety in humans. According to Dr. Boison, "We need to look into the efficacy of different doses of adenosine, the duration of adenosine release, and various time points of intervention."

Future studies also need to demonstrate how long the effects of the adenosine-releasing silk implant will last.

"This work is important because 25-30 percent of people with epilepsy do not have effective therapies. This research may help us to prevent epilepsy in people who suffer some event that places them at risk for the disorder, such as individuals who have experienced head trauma," said Dr. Whittemore.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our epilepsy section for the latest news on this subject.

This study was supported by grants from NINDS (NS061844, NS070359), NIBIB (EB002520), and the U.S. Department of Defense (W81XWH-12-1-0283).

Rebecca L. Williams-Karnesky et al. "Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis." J Clin Invest. doi:10.1172/JCI65636, July 25, 2013.

NIH/National Institute of Neurological Disorders and Stroke

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