P53 Tumor Suppression and Metabolic, Antioxidant Effects

P53 is clearly a tumor suppressor – it is mutated in nearly half of all tumors, and p53 knockouts develop spontaneous tumors at a young age. Researchers from Columbia University have looked into why p53 is a tumor suppressor, and they have come to the conclusion that it's not because of its effects on the cell cycle, senescence or apoptosis. The authors created mice with a version of p53 that cannot be acetylated due to several amino acid substitutions. That form of p53 is no longer able to influence the cell cycle, senescence or apoptosis. It can, however, still affect metabolism and free radical production. The authors found that, unlike p53 knockouts, such mice do not appear to be particularly vulnerable to the development of cancer. They concluded that "unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis." Their paper was published in the June 8, 2012, issue of Cell.

Milk's Resveratrol?

Scientists at the Swiss Ecole Polytechnique Federale de Lausanne have identified an ingredient in milk that may turn out to be a sort of resveratrol for teetotalers. The ingredient, nicotinamide riboside, is a precursor of NAD+, which sirtuins need to work. The authors administered nicotinamide riboside to both cell lines and mice. They found it activated the sirtuins Sirt1 and Sirt3, and that it protected mice from the negative metabolic consequences of a high-fat diet. It also appeared to lead to increased endurance. Other methods to activate NAD+ have not had an effect on sirtuins, most likely because they did not have an effect in the mitochondria. Like resveratrol itself, nicotinamide riboside is present in food at levels that are too low to have a therapeutic benefit. But the authors said their results "indicate that it could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function." Their work appeared in the June 6, 2012, issue of Cell Metabolism.

Finding the Action in RNA Interaction

Scientists at the Germany-based European Molecular Biology Laboratory have identified the complete spectrum of RNA-binding proteins. Of 860 proteins in total, 300 were not previously known to interact with RNA. Almost 50 of those 300 genes, in turn, play roles in a number of diseases. The authors also characterized some of those proteins, and made the unexpected discovery that the RNA interactome, at least in the HeLa cell type, appears to be enriched for proteins with a high level of intrinsic disorder – that is, proteins with regions that do not spontaneously fold into compact shapes, leading to an overall protein form that resembles pearls on a string more than a single complex shape. The authors said the "interactome capture" method they developed for their studies "is broadly applicable to study mRNA interactome composition and dynamics in varied biological settings," which should, in turn, lead to new insights into RNA function and regulation. They published their results in the May 31, 2012, online edition of Cell.

Tuberculosis Vaccine Fights Bladder Cancer

Scientists from the French Institut Pasteur have found a new weapon in the fight against bladder cancer: Bacille Calmette-Guerin, or BCG vaccine, a vaccine that protects against tuberculosis to some degree, although it is not routinely used in the U.S. because the risk of infection is currently low to begin with, and the vaccine's effects are variable and can interfere with detecting the disease if a person becomes infected. The team looked at 55 patients with bladder cancer and found that those with a pre-existing immune response to the BCG vaccine had significantly longer recurrence-free survival than those without. The authors showed that in an animal model, vaccinating with BCG prior to xenotransplanting tumors "markedly improved the response to therapy." Repeated administrations of vaccine were necessary for maximum effect. The work implied that vaccinating patients against tuberculosis prior to other treatment could improve the success of bladder cancer therapies, especially in countries where tuberculosis vaccination is not routine. The work appeared in the June 6, 2012, issue of Science Translational Medicine.

Keeping Commensals in Their Place

Most of the cells in a body may be in a human, but they are not of a human – they are commensals, friendly bacteria that appear to outnumber human cells by a factor of 10 to 1. Commensals are harmless – indeed, they are necessary for normal functioning, especially of the gut. But only as long as they are in their proper location. During disease, they can spread into the bloodstream and to tissues where they are not normally found, causing chronic inflammation as they go. Scientists from the University of Pennsylvania found that innate lymphoid cells, and the interleukin-22 (IL-22) they produce, are critical for keeping commensals where they need to be. When they depleted the gut of mice of innate lymphoid cells, commensals started bolting from the gut via lymph tissue. The wandering bacteria caused "systemic immune responses . . . associated with Crohn's disease and progressive hepatitis C virus infection in patients." Those effects could be prevented by administering IL-22 to the animals. The results appeared in the June 8, 2012, issue of Science.

Gaucher Disease Gene Has Immune Function

A team from the Mount Sinai School of Medicine and Yale University have discovered that the GBA gene, which is mutated in Gaucher disease (GD), has an important role in immune function. GD is a lysosomal storage disorder caused by an inability to metabolize glucoserebrosidase when GBA is not functional. Its most striking features are neurological problems and bone disease, but there are hints of immune effects as well. In their experiments, the authors found that mice lacking the GBA gene specifically in blood stem cells had abnormalities in both their B cells and their T cells. The results "not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregulation through the accumulation of substrates," the authors wrote. Their work appeared in the June 4, 2012, online issue of the Proceedings of the National Academy of Sciences.

ADAM28 Promotes Metastases . . .

Researchers at the Japanese Keio University have made new discoveries about how the prometastatic ADAM28 exerts its effects. Using an interaction screen, they identified the pro-apoptotic von Willebrand factor as a binding partner of ADAM28. Through cell culture and animals studies, they reached the conclusion that when ADAM28 and von Willebrand factor bind, the latter is inactivated. That leads to increased lung metastasis, "probably by promoting carcinoma cell survival within the blood vessels." The team published their study in the June 8, 2012, issue of the Journal of the National Cancer Institute.

. . . HIV Drug May Block Them

Researchers from the Thomas Jefferson University Kimmel Cancer Center have discovered that in cell cultures and mouse models, treating some breast cancer subtypes with HIV drugs decreased the likelihood those cancers would metastasize. The drugs, Celsentri/Selzentry (maraviroc, ViiV Healthcare Co., which is a joint venture between Pfizer Inc. and GlaxoSmithKline plc) and vicriviroc (Merck & Co. Inc.), target the chemokine receptor CCR5, which is a co-factor for HIV entry. The authors first screened more than 2,000 breast cancer tissue samples and found that CCR5 and its ligand were overexpressed in basal and HER2-positive tumors. Treatment with the CCR5 antagonists did not kill breast cancer cells, but it did make them less invasive in cell culture and decreased lung metastases in an animal xenograft model. The authors said that "our preclinical studies provide the rational basis for studying the use of CCR5 antagonists as new treatments to block the dissemination of basal breast cancers." Their work appeared in the May 25, 2012, advance online edition of Cancer Research.

Interferon's Effects on Depression

One of the side effects of interferon-gamma treatment, and one of the reasons companies are trying so hard to develop interferon-free regimens for the treatment of hepatitis C, is that about a quarter of patients develop symptoms of depression from treatment with the immune stimulator, which can be severe enough to lead to suicide. Scientists from the German University of Essen have used gene expression profiling to search for the genetic underpinnings of that effect. They analyzed blood samples from 50 hepatitis C patients being treated with interferon-alpha2a plus ribavirin, 22 patients with depression and 11 healthy controls. They identified 15 genes that were up-regulated in hepatitis patients who developed depression compared to those who did not. Six of those genes have been linked to depression in other studies as well. The authors said their work provides insight into depression in response to interferon treatment, as well as a possible contribution of inflammation to major depression in general. The work appeared in the June 6, 2012, issue of PLoS ONE.

Activating Brown Fat: Hold the Ephedrine

Energy-burning brown fat improves metabolism, and so activating it artificially is one goal of obesity researchers. Researchers from the Joslin Diabetes Center have shown, however, that ephedrine, a drug which activates the sympathetic nervous system, is not the way to do so. The team either administered ephedrine to healthy volunteers, or exposed them to cold temperatures. Both ephedrine and cold exposure increased energy expenditure, but only cold did so in part via activating brown fat cells. Both interventions also raised blood pressure, but cold had fewer systemic effects overall. The authors concluded that "agents that mimic cold activation of [brown fat cells] could provide a promising approach to treating obesity while minimizing systemic effects." Their work appeared in the June 4, 2012, online issue of the Proceedings of the National Academy of Sciences.

– By Anette Breindl, Science Editor