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Archive - Jan 2012


January 12th

First Major Mutation Associated with Hereditary Prostate Cancer Risk

After a 20-year quest to find a genetic driver for prostate cancer that strikes men at younger ages and runs in families, researchers have identified a rare, inherited mutation linked to a significantly higher risk of the disease. A report on the discovery, published in the January 12, 2012 issue of the New England Journal of Medicine, was led by investigators at the Johns Hopkins University School of Medicine and the University of Michigan (U-M) Health System. The research team found that men who inherit this mutation have a 10 to 20 times higher risk of developing prostate cancer. While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional or earlier screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer. “This is the first major genetic variant associated with inherited prostate cancer,” says Dr. Kathleen A. Cooney, professor of internal medicine and urology at the U-M Medical School, one of the study’s two senior authors. “It’s what we’ve been looking for over the past 20 years,” adds Dr. William B. Isaacs, professor of urology and oncology at the Johns Hopkins University School of Medicine, the study’s other senior author. “It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and previous studies have provided inconsistent results.” For this study, the researchers collaborated with Dr. John Carpten, at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, who used the latest technology to sequence the DNA of more than 200 genes in a human chromosome region known as 17q21-22. Dr. Cooney, working with Dr.

January 11th

Detailed Look at Key Proteasome Particle

Important new information on one of the most critical protein machines in living cells has been reported by a team of researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) at Berkeley. The researchers have provided the most detailed look ever at the “regulatory particle” used by the protein machines known as proteasomes to identify and degrade proteins that have been marked for destruction. The activities controlled by this regulatory particle are critical to the quality control of cellular proteins, as well as to a broad range of vital biochemical processes, including transcription, DNA repair, and the immune defense system. “Using electron microscopy and a revolutionary new system for protein expression, we have determined at a subnanometer scale the complete architecture, including the relative positions of all its protein components, of the proteasome regulatory particle,” says biophysicist Dr. Eva Nogales, the research team’s co-principal investigator. “This provides a structural basis for the ability of the proteasome to recognize and degrade unwanted proteins and thereby regulate the amount of any one type of protein that is present in the cell.” Says the team’s other co-principal investigator and corresponding author, biochemist Dr. Andreas Martin, “While the biochemical function of many of the proteasome components have been determined, and some subnanometer structures have been identified, it was unclear, before now, which component goes where and which components interact with one another.

January 8th

Overexpression of Two Genes Is Associated with MeCP2-Related Anxiety

The anxiety and behavioral issues associated with excess MeCP2 protein result from overexpression of two genes (Crh [corticotropin-releasing hormone] and Oprm 1 [mu-opioid receptor MOR 1]), which may point the way to treating these problems in patients with too much of the protein, said Baylor College of Medicine (BCM) scientists in a report that appears online in the journal Nature Genetics. Much of the reported work was done at the Jan and Dan L. Duncan Neurological Research Institute (NRI) at Texas Children's Hospital. MeCP2 is a "Goldilocks" in the protein world. When the protein is lacking or defective, girls develop the neurological disorder Rett syndrome early in life. Too much protein results in the more recently identified MeCP2 duplication syndrome, which usually affects boys, who may inherit the gene duplications either from their mothers or, in rare cases, develop it sporadically. In both cases, anxiety and social behavioral deficits are typical of those with the disease, along with other motor problems and cognitive defects. "This is a nice example of a translational story," said Dr. Rodney Samaco, assistant professor of molecular and human genetics at BCM and first author of the paper. "We first identified the mouse model for MeCP2 duplication syndrome and then found people with the disorder in the clinic. We went back to the lab and found out that MeCP2 was indeed the major contributor to this phenotype in patients. We have now identified two genes involved in two major symptoms of the syndrome. Eventually, we may take the information back to the clinic to develop a treatment for patients." "Loss or gain of MeCP2 affects the expression of hundreds of genes, but discovering that two genes are the culprits in mediating anxiety and social behavioral problems is surprising," said Dr.

January 4th

New Gene That Regulates Body Weight Identified

Dr. Abraham Kovoor was studying a brain protein, called RGS9-2, that he had previously related to the involuntary, random, and repetitive body movements that are side effects of drugs used to treat Parkinson's disease and schizophrenia. While studying these side effects, which are collectively called dyskinesia, Dr. Kovoor, an assistant professor in the University of Rhode Island's College of Pharmacy, discovered that RGS9-2 also plays a role in regulating body weight. Results of the study were published online on November 23, 2011 in PLoS ONE. Dr. Kovoor and his collaborators found that humans with a gene variation that could reduce RGS9 2 levels had a significantly higher body mass index. Similarly, when they examined a strain of mice in which the RGS9 2 gene was deleted, so that these mice do not make RGS9 2 protein, they found that these mice weighed more than the wild-type strain and the percentage of body fat was much greater. Conversely, when RGS9-2 protein is over-expressed in rats, they found that the rats lost weight. Because RGS9-2 is normally expressed in the brain's striatum, a section of the brain involved in both motor control and reward responses, Dr. Kovoor and his fellow researchers thought that the weight gain could be a result of an increased reward response triggered during eating. "You would expect more eating from the mice without RGS9-2 (because they were the ones that gained weight), but that was not the case," Dr. Kovoor said. "Studies with humans, rats, and mice implicate RGS9-2 as a factor in regulating body weight. But we had to look at another factor other than feeding behavior. Our research shows that the striatum, through RGS9-2, has a role in regulating body weight that is independent of the motivation, movement, and reward responses," Dr. Kovoor continued.

January 2nd

Advance in Study of Duchenne Muscular Dystrophy

Researchers describe how increased production of a microRNA promotes progressive muscle deterioration in a mouse model of Duchenne muscular dystrophy (DMD), according to a study published online on January 2, 2012 in the Journal of Cell Biology. As DMD patients age, their damaged muscle cells are gradually replaced by collagen-rich, fibrous tissue. This muscle fibrosis is partly induced by the growth factor TGF-beta, which is highly activated in DMD patients, though exactly how this cytokine promotes fibrogenesis is unclear. Dr. Pura Muñoz-Cánoves and colleagues examined the role of miR-21, a microRNA whose production is stimulated by TGF-beta signaling. miR-21 was upregulated in the collagen-producing fibroblasts of both DMD patients and mice that develop disease symptoms similar to human muscular dystrophy (so-called mdx mice). Inhibiting miR-21 reduced collagen levels and prevented, or even reversed, fibrogenesis in diseased mice, whereas mdx mice overexpressing the microRNA produced more collagen and developed fibrotic muscles at earlier ages. The researchers also discovered that TGF-beta activity and miR-21 production were regulated by the balance of two extracellular factors: uPA—a protease that activates TGF-beta—and its inhibitor PAI-1. mdx mice developed fibrotic muscles more quickly in the absence of PAI-1, but these symptoms could be reversed by inhibiting uPA with a drug or a specific siRNA. In addition to producing more collagen, PAI-1–null fibroblasts also proliferated rapidly because the extra miR-21 induced by active TGF-beta inhibited the tumor-suppressive phosphatase PTEN. TGF-beta inhibitors prevent muscle fibrosis, but have damaging side effects; this study suggests that uPA or miR-21 may make attractive alternative drug targets. Dr.

January 1st

Mutations in ATM Gene May Increase Risk of Hereditary Pancreatic Cancer

Mutations in the ATM gene may increase the hereditary risk for pancreatic cancer, according to data published online on December 29, 2011 in Cancer Discovery, the newest journal of the American Association for Cancer Research. Pancreatic cancer is one of the most morbid cancers, with less than 5 percent of those diagnosed with the disease surviving to five years. Approximately 10 percent of pancreatic cancer patients come from families with multiple cases of the disease. "There was significant reason to believe this clustering was due to genetics, but we had not, to this point, been able to find the causative genes that explained the cluster of pancreatic cancer for a majority of these families," said lead author Dr. Alison Klein, associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and director of the National Familial Pancreas Tumor Registry. Dr. Klein and colleagues, including Dr. Kenneth Kinzler, used next-generation sequencing, including whole-genome and whole-exome analyses, and identified ATM gene mutations in two kindreds with familial pancreatic cancer. When these initial findings were examined in a large series for patients, ATM mutations were present in 4 of 166 subjects with pancreatic cancer but were absent in 190 spousal control subsets. Knowledge of the potential significance of ATM gene mutations could lead to better screening for pancreatic cancer, the fourth most common cause of cancer-related death. However, there are currently no recommended screening tests. Many doctors use endoscopy as a screening tool for pancreatic cancer, but researchers are still evaluating this technique in clinical trials.