HRAS, NRAS are KRAS enablers

KRAS is among the most frequently mutated genes in cancer. Now, researchers from New York University have found that in cells with mutated KRAS, the normal versions of two other members of the Ras family – HRAS and NRAS – contribute to the out-of-control growth of KRAS mutated cells. One of the functions of ras proteins is to activate pathways that check for DNA damage, and cancer cells including KRAS mutated cells are highly dependent on such DNA damage checks. The authors found that when they knocked down wild-type NRAS or HRAS in KRAS mutated cells, the cells no longer checked their DNA for damage, and this in turn made them more sensitive to the DNA-damaging chemotherapy irinotecan. The authors said that their findings suggest that the dependence of KRAS mutated cells on wild-type HRAS and NRAS “can be exploited to specifically sensitize KRAS-driven cancers to DNA damage-inducing agents.” Their findings appeared in the Feb. 10, 2014, issue of Cancer Cell.

When the fountain of youth gets old

Separate teams, one from the University of Colorado and one from Stanford University and the Canadian University of Toronto, have gained new insights into the aging of muscle stem cells, and how to reverse it. Declining strength is frequently one aspect of aging, and the resulting reduced mobility both leads to lower quality of life and speeds up other aspects of the aging process. In their studies, the authors compared muscle stem cells from old and young mice and found that two-thirds of the stem cells from the aged animals were defective in their regenerative capacities. However, stem cells could be rejuvenated by simultaneously culturing them on hydrogels and inhibiting a kinase, p38 map kinase, that the authors identified as being behind their functional decline. The authors concluded that “these findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.” The papers appeared back to back in the Feb. 16, 2014, issue of Nature.

Why the fountain of youth gets old

In a third paper, a team from the Spanish Pompeu Fabra University described the reason why geriatric muscle stem cells decline in their function in the first place. To retain the ability to regenerate, stem cells must refrain from regenerating most of the time – they must be in a so-called quiescent state. The researchers found that muscle stem cells from old mice were less able to maintain that state, and repressed proliferation instead by switching to an irreversible senescent state. This switch happened when the cells lost the ability to inhibit the expression of the aging biomarker p16INK4a. Silencing p16INK4a restored the cells’ ability to divide and produce daughter cells. The authors concluded that maintaining stem cell capacities “depends on the active repression of senescence pathways.” Their work appeared in the Feb. 13, 2014, issue of Nature.

Good news about amyloids and memories

Amyloids’ reputation in memory is not a good one, to say the least. But scientists at the Stowers Institute for Medical Research have demonstrated that some amyloids are critical for memory formation, at least in fruit flies. Amyloids are protein aggregates with specific structural features, and for long-term memories to form in the flies, the protein Orb2 has to fold into such amyloid shapes. In their work, the authors demonstrated that there was a specific folding conformation of Orb2, Orb2A, that seeded the formation of amyloid by another conformation, Orb2B. The authors suggested that memory formation could be influenced by controlling the amount of Orb2A, which occurs fairly rarely under natural circumstances. Their work appeared in the Feb. 11, 2014, issue of PLoS Biology.

Heart damage through PTSD

Scientists at the Institute for Systems Biology have identified changes in the transcriptome of the heart that occur as a result of social stress, which they used to model the effects of post-traumatic stress disorder (PTSD). In their study, the authors repeatedly exposed docile mice to more aggressive ones, and looked at gene expression changes in cardiac tissue that resulted from such stress. They found that such changes were very rapid, starting after just a single exposure, and that they differed by mouse strain. Repair processes were also initiated rapidly, within a few days of the start of stress. The authors acknowledged that “whether this type of injury has any long-term effects on heart function is yet to be determined,” but the results demonstrated that PTSD has physiological consequences for the heart, and that those consequences are influenced by genetic factors. The work appeared in the Feb. 10, 2014, advance online issue of the Proceedings of the National Academy of Sciences.

Novel tumor suppressor found

By comparing the genomes of twin sisters, one of whom had leukemia and one of whom did not, researchers at the Cincinnati Children’s Hospital Medical Center and the Chinese Beijing Institute of Genomics have identified a new SETD2 as a new tumor suppressor gene. Gene rearrangements underlie many cancers, but a single gene rearrangement is usually not enough to lead to cancer. In their work, the authors looked at the genomes of the twins, both of whom had a MLL-NRIP3 fusion gene, which can lead to leukemia. They found that in addition to the fusion gene, the leukemic twin also had mutations in both copies of the SETD2 genes. The same mutation was found in about 6 percent of patients with acute leukemia, and work in cell culture showed that knockdown of SETD2 contributed to both the initiation and progression of leukemia. The authors concluded that “our study provides compelling evidence for SETD2 as a new tumor suppressor.” Their work appeared in the Feb. 9, 2014, issue of Nature Genetics.

Making platelets . . .

Researchers from the Japanese Kyoto University have developed a method that has allowed them to make large numbers of platelets from induced pluripotent stem (iPS) cells. Platelets, which are critical for blood clotting, currently cannot be stored for very long, and blood shortages are constantly looming as demand outstrips supply. In their work, the authors described generating stable platelet progenitors through the overexpression of anti-apoptotic proteins and the Yamanaka reprogramming factor c-Myc. Halting the overexpression of those proteins, in turn, led the cells to produce large numbers of platelets. Such progenitors could produce platelets “with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo” for several months, even after they were frozen and re-thawed. The authors “believe that . . . it will be feasible though to achieve clinically effective platelet transfusion without a requirement for donor blood.” Their work appeared in the Feb. 13, 2014, issue of Cell Stem Cell.

. . . Or preventing their effects

Researchers from the University of Michigan and the University of California at Los Angeles have developed a nanodevice that combines two catalytic molecules, creating a tandem catalyst that could prevent blood clotting. Biological processes often occur as amplifying cascades, and so the ability to have two catalytic factors in close proximity would allow for the creation of catalysts that can work under physiological conditions. In their work, the authors combined two such catalysts on grapheme. One was hemin, a molecular catalyst, while the other was glucose oxidase, an enzymatic catalyst. Together, the authors said the two catalysts “can readily enable the continuous generation of nitroxyl, an antithrombotic species, from physiologically abundant glucose and L-arginine” in the blood. They also showed that their material could be used coat polyurethane, which means that in principle it might be used as a coating for medical devices to prevent blood clotting. The work appeared in the Feb. 11, 2014, issue of Nature Communications.

Zinc zings cartilage

A team from the Korean Gwangju Institute of Science and Technology has implicated zinc, and its transport protein ZIP8, in osteoarthritis, which is characterized by cartilage breakdown. Osteoarthritis is the most frequent form of arthritis and affects tens of millions of people in the U.S. alone, but no disease-modifying therapies exist. In their work, the authors showed that the zinc transporter ZIP8 was upregulated in osteoarthritis, and that this upregulation led to increased influx of zinc, which is necessary for proteases to function. Those proteases, in turn, degrade the extracellular matrix, which is the root of the trouble in osteoarthritis. The authors found that overexpressing the zinc transporter caused cartilage destruction, while knocking it out prevented injury-induced osteoarthritis. They concluded that targeting the zinc transporter might be a useful therapeutic approach to osteoarthritis. Their work appeared in the Feb. 13, 2014, issue of Cell.

Innate autoimmunity

Scientists from the Japanese Kyoto University have elucidated how the innate immune system contributes to some forms of autoimmunity. Though full-blown autoimmunity is mediated by the T cells and B cells of the adaptive immune system, there have long been hints that the innate immune system helps get the ball rolling in such disorders. In their work, the team showed that mice with mutations of the intracellular double-stranded RNA sensor MDA5, which normally guards against viral attack, spontaneously developed lupus-like symptoms. The mice did not have to contract a viral infection for the autoimmune symptoms to start. In fact, the authors noted, “this MDA5 mutant could activate signaling in the absence of its ligand but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.” They were published in the Feb. 13, 2014, issue of Immunity.

By Anette Breindl, Science Editor