Syndicate content

Archive - Mar 13, 2014


Plant Breakthrogh: Auxin Sensing and Signaling Complex Discovered on Plant Cell Surface

Auxin, a small molecule, is a plant hormone discovered by Charles Darwin about 100 years ago. Over the years that followed it became understood to be the most important and versatile plant hormone controlling nearly all aspects of plant growth and development, such as bending of shoots toward the source of light (as discovered by Darwin), formation of new leaves, flowers, and roots, growth of roots, and gravity-oriented growth. Just how a small molecule like auxin could play such a pivotal role in plants baffled plant biologists for decades. Then, about ten years ago, an auxin sensing and signaling system was discovered in the cell's nucleus, but it still could not explain all the diverse roles of auxin. Now, plant cell biologists at the University of California (UC), Riverside, have discovered a new auxin sensing and signaling complex, one that is localized on the cell surface rather than in the cell's nucleus. The discovery provides new insights into the mode of auxin action, the researchers say. "This is a new milestone in auxin biology and will ignite interest in the field," said Dr. Zhenbiao Yang, a professor of cell biology in the Department of Botany and Plant Sciences, and the leader of the research project. "Our findings conclusively demonstrate the existence of an extracellular auxin sensing system in plants, which had long been proposed but remained elusive. Further, we have uncovered the decades-long mystery of how ABP1, an auxin-binding protein, works to control plant developmental processes." ABP1 was identified more than 40 years ago, but its role was hotly debated among plant biologists because its mode of action remained unclear — until the recent discovery by Yang's team.

MicroRNA-34 Genes Cooperate with p53 to Suppress Prostate Cancer

Cornell researchers report they have discovered direct genetic evidence that a family of genes, called microRNA-34 (miR-34), are bona fide tumor suppressors. The study was published online in the journal Cell Reports on March 13, 2014. Previous research at Cornell and elsewhere has shown that another gene, called p53, acts to positively regulate miR-34. Mutations of p53 have been implicated in half of all cancers. Interestingly, miR-34 is also frequently silenced by mechanisms other than p53 in many cancers, including those with p53 mutations. The researchers showed in mice how interplay between genes p53 and miR-34 jointly inhibits another cancer-causing gene called MET. In absence of p53 and miR-34, MET overexpresses a receptor protein and promotes unregulated cell growth and metastasis. This is the first time this mechanism has been proven in a mouse model, said Dr. Alexander Nikitin, a professor of pathology in Cornell’s Department of Biomedical Sciences and the paper’s senior author. Chieh-Yang Cheng, a graduate student in Dr. Nikitin’s lab, is the paper’s first author. In a 2011 Proceedings of the National Academy of Sciences paper, Dr. Nikitin and colleagues showed that p53 and miR-34 jointly regulate MET in cell culture but it remained unknown if the same mechanism works in a mouse model of cancer (a special strain of mice used to study human disease). The findings suggest that drug therapies that target and suppress MET could be especially successful in cancers where both p53 and miR-34 are deficient. The researchers used mice bred to develop prostate cancer, then inactivated the p53 gene by itself, or miR-34 by itself, or both together, but only in epithelium tissue of the prostate, as global silencing of these genes may have produced misleading results.

Gene Variants Protect Against Relapse after Treatment for Hepatitis C

Researchers at the Sahlgrenska Academy in Sweden have identified a gene, which explains why certain patients with chronic hepatitis C do not experience relapse after treatment. The discovery may contribute to more effective treatment. More than 100 million humans around the world are infected with hepatitis C virus. The infection gives rise to chronic liver inflammation, which may result in reduced liver function, liver cirrhosis, and liver cancer. Even though anti-viral medications often efficiently eliminate the virus, the infection recurs in approximately one fifth of the patients. Dr. Martin Lagging and co-workers at the Sahlgrenska Academy have studied an enzyme called inosine trifosfatas (ITPase), which normally prevents the incorporation of defective building blocks into RNA and DNA. Unexpectedly, they found that the gene encoding for ITPase (ITPA) had significance for the treatment outcome in chronic hepatitis C virus infection. Earlier studies had shown that approximately one third of all people carry variants of the ITPA gene that result in reduced ITPase activity. The research team at the Sahlgrenska Academy showed that patients with these gene variants exhibited a more than a five times lower risk of experiencing relapse after treatment. The study encompassed over 300 patients and was carried out in cooperation with hepatitis researchers in several Nordic countries. “Relapse after completed treatment is a significant problem in chronic hepatitis C, and the results may contribute to explaining why the infection recurs in many patients. Our hypothesis is that a low ITPase activity results in defective nucleotides being incorporated into the virus RNA, which makes the virus unstable,” Dr. Lagging said. According to Dr. Lagging, the discovery may also have significance for other virus infections.

Relationship Between Gut Bacteria and Blood Cell Development Helps Immune System Fight Infection

The human relationship with microbial life is complicated. At almost any supermarket, you can pick up both antibacterial soap and probiotic yogurt during the same shopping trip. Although there are types of bacteria that can make us sick, Caltech professor of biology and biological engineering Dr. Sarkis Mazmanian and his team are most interested in the thousands of other bacteria—many already living inside our bodies—that actually keep us healthy. His past work in mice has shown that restoring populations of beneficial bacteria can help alleviate the symptoms of inflammatory bowel disease, multiple sclerosis, and even autism. Now, he and his team have found that these good bugs might also prepare the immune cells in our blood to fight infections from harmful bacteria. In the recent study, published on March 12, 2014 in the journal Cell Host & Microbe, the researchers found that beneficial gut bacteria were necessary for the development of innate immune cells—specialized types of white blood cells that serve as the body's first line of defense against invading pathogens. In addition to circulating in the blood, reserve stores of immune cells are also kept in the spleen and in the bone marrow. When the researchers looked at the immune cell populations in these areas in so-called germ-free mice, born without gut bacteria, and in healthy mice with a normal population of microbes in the gut, they found that germ-free mice had fewer immune cells—specifically macrophages, monocytes, and neutrophils—than healthy mice. Germ-free mice also had fewer granulocyte and monocyte progenitor cells, stemlike cells that can eventually differentiate into a few types of mature immune cells. And the innate immune cells that were in the spleen were defective—never fully reaching the proportions found in healthy mice with a diverse population of gut microbes.

Stem Cells Embedded in Sutures May Improve Healing in Achilles Tendon Injuries

Researchers have found that sutures embedded with stem cells led to quicker and stronger healing of Achilles tendon tears than traditional sutures, according to a new study published in the March 2014 issue of Foot & Ankle International (published by SAGE). Achilles tendon injuries are common for professional, collegiate, and recreational athletes. These injuries are often treated surgically to reattach or repair the tendon if it has been torn. Patients have to keep their legs immobilized for a while after surgery before beginning their rehabilitation. Athletes may return to their activities sooner, but risk rerupturing the tendon if it has not healed completely. Drs. Lew Schon, Samuel Adams, and Elizabeth Allen and researchers Margaret Thorpe, Brent Parks, and Gary Aghazarian from MedStar Union Memorial Hospital in Baltimore, Maryland, conducted the study. They compared traditional surgery, surgery with stem cells injected in the injury area, and surgery with special sutures embedded with stem cells in rats. The results showed that the group receiving the stem cell sutures healed better. "The exciting news from this early work is that the stem cells stayed in the tendon, promoting healing right away, during a time when patients are not able to begin aggressive rehabilitation. When people can't fully use their leg, the risk is that atrophy sets in and adhesions can develop which can impact how strong and functional the muscle and tendon are after it is reattached," said Dr. Schon. "Not only did the stem cells encourage better healing at the cellular level, the tendon strength itself was also stronger four weeks following surgery than in the other groups in our study," he added.

Scientists ID Extracellular Matrix Proteins That Aid Metastasis

About 90 percent of cancer deaths are caused by tumors that have spread from their original locations. This process, known as metastasis, requires cancer cells to break loose from their neighbors and from the supportive scaffold that gives tissues their structure. MIT cancer biologists have now discovered that certain proteins in this structure, known as the extracellular matrix, help cancer cells make their escape. The researchers identified dozens of proteins that surround highly metastatic tumors, but not less aggressive tumors, and found that four of those proteins are critical to metastasis. The findings could lead to new tests that predict which tumors are most likely to metastasize, and may also help to identify new therapeutic targets for metastatic tumors, which are extremely difficult to treat. “The problem is, all the current drugs are targeted to primary tumors. Once a metastasis appears, in many cases, there’s nothing you can do about it,” says Dr. Richard Hynes, leader of the research team and a member of MIT’s Koch Institute for Integrative Cancer Research. “In principle, one could imagine interfering with some of these extracellular proteins and blocking metastasis in a patient. We’re a long way from that, but it’s not inconceivable.” Koch Institute postdoc Dr. Alexandra Naba is the lead author of the study, which appears in the March 11 online edition of the journal eLife. Other authors are Dr. Steven Carr, director of the Proteomics Platform at the Broad Institute; Dr. Karl Clauser, a research scientist at the Broad Institute; and Dr. John Lamar, a research scientist at the Koch Institute. The extracellular matrix is made mostly of collagens, proteins that provide structural support for living tissues.

Protein Key to Cell Motility Has Implications for Halting Cancer Metastasis

"Cell movement is the basic recipe of life, and all cells have the capacity to move," says Roberto Dominguez, Ph.D., professor of Physiology at the Perelman School of Medicine, University of Pennsylvania. Motility – albeit on a cellular spatial scale -- is necessary for wound healing, clotting, fetal development, nerve connections, and the immune response, among other functions. On the other hand, cell movement can be deleterious when cancer cells break away from tumors and migrate to set up shop in other tissues during cancer metastasis. The Dominguez team, with postdoctoral fellow David Kast, Ph.D., and colleagues, reported online ahead of print on Marh 2, 2014 in Nature Structural & Molecular Biology how a key cell-movement protein called IRSp53 is regulated in a resting and active state, and what this means for cancer-cell metastasis. "We characterized how IRSp53 connects to the cell-motility machinery," says Dr. Kast. "It does this by starting the formation of cell filopodia - extensions that form when a cell needs to move." "Cells move like an inchworm," explains Dr. Dominguez. "Filopodia are at the leading edge of moving cells." The trailing end of the cell follows the move forward through contraction of actin and myosin in the cytoskeleton, much like muscle contraction. A cell pushes out the leading edge of its membrane, and sticks it down on whatever it is moving across, namely other cells, and then moves the cell body along, unsticking the back end. This sets the cell up for its next move. IRSp53 contains a region called a BAR domain that binds to and shapes cell membranes. Other parts of the protein connect it to the cytoskeleton (internal bits that give a cell structure and shape). Together, through the binding of cell membranes and other proteins IRSp53 regulates cell movement.

Turing’s Far-Reaching Theory of Morphogenesis Validated 60 Years After His Death

British mathematician Alan Turing’s (image) accomplishments in computer science are well known—he’s the man who cracked the German Enigma code, expediting the Allies’ victory in World War II. He also had a tremendous impact on biology and chemistry. In his only paper in biology, Turing proposed a theory of morphogenesis, or how identical copies of a single cell differentiate, for example, into an organism with arms and legs, a head and tail. Now, 60 years after Turing’s death, researchers from the University of Pittsburgh (Pitt) and Brandeis University have provided the first experimental evidence that validates Turing’s theory in cell-like structures. The team published its findings online in PNAS on March 10. Turing, in 1952, was the first to offer an explanation of morphogenesis through chemistry. He theorized that identical biological cells differentiate and change shape through a process called intercellular reaction-diffusion. In this model, chemicals react with each other and diffuse across space—say between cells in an embryo. These chemical reactions are managed by the interaction of inhibitory and excitatory agents. When this interaction plays out across an embryo, it creates patterns of chemically different cells. Turing predicted six different patterns could arise from this model. At Brandeis, Dr. Seth Fraden, professor of physics, and Dr. Irv Epstein, professor of chemistry, created rings of synthetic, cell-like structures with activating and inhibiting chemical reactions to test Turing’s model. Pitt’s Dr. G. Bard Ermentrout, University Professor of Computational Biology and professor of mathematics in the Kenneth P. Dietrich School of Arts and Sciences, undertook mathematical analysis of the experiments. The researchers observed all six patterns plus a seventh unpredicted by Turing.