A Tadpole Tail's Tale: Regeneration by ROS

Scientists from the British University of Manchester have discovered a surprising requirement for successful regeneration in amphibians: reactive oxygen species (ROS) or free radicals, which are more often associated with cell damage than repair. In previous studies, the team had shown that tail injury in tadpoles – which can regenerate their tails within a week after amputation – induced changes in gene expression that led to high levels of ROS in the injured cells. In their new study, they showed that hydrogen peroxide production in cells was quickly increased after a tail injury, and stayed high for the duration of the regenerative processes. Lowering hydrogen peroxide levels in cells reduced cell proliferation and impaired tail repair. The findings appeared in the Jan. 13, 2013, issue of Nature Cell Biology.

New Heart Stress Protector

Researchers from the University of California at San Diego have identified a protein that appears to be able to protect the heart from damage when it is under ischemic stress, such as might be the case after a heart attack. The protein, A-kinase interacting protein 1 (AKIP1), helps protein kinase A, which is something of a master regulator of cell function in heart cells. The authors found that AKIP1 was upregulated in heart muscle cells under stress conditions, especially in the mitochondria, where it interacted with another factor, Apoptosis Inducing Factor. Mitochondria expressing high levels of AKIP1 were better able to deal with ischemic stress, and the authors concluded their findings "highlight AKIP1 as a critical molecular regulator and a therapeutic control point for stress adaptation in the heart." They appeared in the Jan. 14, 2013, advance online edition of the Proceedings of the National Academy of Sciences.

Liver Plays Role in Wasting

Scientists from the German Cancer Research Center have identified a growth factor in the liver that is involved in the metabolic changes of cachexia, the wasting that accompanies many serious diseases including cancer and AIDS. Previous cachexia research has often focused on fat and muscle tissue, but cachexia patients often have fatty livers, which suggested that the liver may have a driving role in the disorder. The authors found that in mice, cachexia activated the transcription factor TSC22D4, which in turn decreased the levels of very low-density lipoprotein (VLDL), an important carrier of fats in the blood. That lack of VLDL deprived the body of metabolic building blocks and causing further wasting. The work showed that "specific [liver] transcriptional programs significantly impact overall systemic energy availability and thereby further propagate an energy-deficient wasting condition in response to tumor burden." Their work appeared in the Jan. 11, 2013, online issue of EMBO Molecular Medicine.

GWAS to Gene Function Still a Big Fat Problem

There is no doubt that the fat mass and obesity associated or Fto gene is associated with, body mass index, obesity and diabetes. The relationship has been validated in a number of different genomewide association studies. But why the protein affects fat mass and obesity has remained unclear, in part because knocking the gene out during development is often lethal. Now, researchers from the British Medical Research Council, Harwell, have conducted a series of more specific knockout experiments that begin to shed light on where Fto does and does not play a role. Adult-onset global loss of the gene affected lean mass, but the effect seems to be independent of its effects on food intake. Interestingly, deleting the gene only in the hypothalamus, which is a critical brain structure for the control of food intake and metabolism, had only minimal effects. In a review that accompanied the paper, researchers from the German Helmholtz center said that the paper, along with others that have looked at Fto function, "highlight both the considerable challenges of, and the need for, careful and often time-consuming functional studies before the value of GWAS candidate genes can be truly appreciated." Paper and review appeared in the Jan. 3, 2013, issue of PLoS Genetics.

Turbocharging EGFR Inhibitors

Scientists from the Fox Chase Cancer Center have been able to potentiate the effects of EGF receptor inhibitors by deleting genes that are a part of the cholesterol biosynthesis pathway. Activated epidermal growth factor receptors can drive cancer cell growth, and are targeted by several drugs such as Erbitux (cetuximab, Eli Lilly and Co.). In their work, the authors showed that cells lacking a key enzyme for cholesterol biosynthesis were much more sensitive to Erbitux than wild-type cells. They also showed that in knockout mice lacking the cholesterol synthesis gene, the EGF receptor was inactive. Cancer cells are dependent on cholesterol synthesis because they are constantly making new membranes for cell division, and so the authors hope their findings point to a way to potentiate EGFR-targeting cancer drugs. The findings were published in the January 2013, print issue of Cancer Discovery.

Can BCR-ABL Be Forced to Kill Itself?

A team at Duke University has engineered a new way to fight the cancer that results when a cell acquires the so-called Philadelphia chromosome, which results in a constantly active ABL kinase. BCR-ABL inhibitors, from Gleevec (imatinib, Novartis AG) onward, have transformed the treatment of such disease. But the kinase can and does develop resistance mutations in a subset of patients. In their work, the authors engineered the pro-apoptotic protein caspase to respond to activated ABL kinase. "Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells," the authors explained, "this approach selectively eliminates leukemic cells regardless of drug-resistant mutations." While the delivery of genes for such engineered caspases is itself not trivial, the authors said that their approach might be particularly useful to decontaminate bone marrow prior to autologous transplants. They published their work in the Jan. 14, 2013, advance online edition of the Proceedings of the National Academy of Sciences.

Drug Resistance Gene & Chromosomal Instability

Researchers from the University of Iowa have linked a region of chromosomal instability to drug resistance in multiple myeloma cells. Cancer cells often have chromosomal instability, where whole chromosomes, or significant chunks thereof, are gained or lost during cell division, leading to cells with the wrong number of chromosomes. The authors looked at both genes whose expression correlated with chromosomal instability, and with drug resistance, since both are predictors of a poor outcome. They found that high expression levels of the drug efflux pump NEK2 correlated with chromosomal instability, and knocking down NEK2 RNA in multiple myeloma cells fought drug resistance and led to increased cell death. The authors said their findings "have the potential to translate into very important prognostic and therapeutic clinical tools. Overexpression of NEK2 has been shown to be associated with aggressive cancer behavior and poor prognosis in many malignancies and, therefore, our findings should also apply to other hematologic malignancies and solid tumors." Their work appeared in the Jan. 14, 2013, issue of Cancer Cell.

Micro Deletion Leads to MicroRNA Changes

Microdeletions of the chromosomal region 22q11 .2 can result in more than 180 different health issues. Those issues include cognitive deficits, and the microdeletion increases its carriers' risk for schizophrenia. Now, a team from Columbia University has identified a microRNA that appears to be the key to why this microdeletion is so harmful. They showed that missing one copy of the 22q11 .2 region reduces the levels of miRNA185 by far more than the 50 percent that would be expected. MiR185 targets the Golgi apparatus, where proteins are packaged prior to transport into different parts of the cell. Mice missing miR185 had defects in the development of their dendritic spines, which form the connections between neurons and so are critical for information processing in the brain. The authors said their experiments "illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction." They published their work in the Jan. 17, 2013, issue of Cell.

TB Needs Spoonful of Sugar After All

Scientists from Weill Cornell College have published results that suggested the tuberculosis bacterium may rely on glucose more than is currently realized, especially in chronic infections. Currently, it is assumed that tuberculosis lives mainly off of fatty acid metabolism. But in their work, the authors showed the bacterium expresses two separate enzymes that phosphorylate glucose, and that bacteria lacking those enzymes could initially establish infections in mice, but could not persist in the way that is typical of tuberculosis. The team concluded that Mycobacterium tuberculosis is more flexible than is currently realized in how it meets its energy needs. They published their findings in the Jan. 10, 2013, online edition of PLoS Pathogens.

Better Model for Tauopathy?

Researchers from the University of Pennsylvania have shown that tau tangles can form from synthetic tau seeds in an Alzheimer's disease animal model, and that such artificially seeded tau tangles are more like the tangles seen in Alzheimer's disease victims in several of their molecular characteristics. Using synthetic seeds allowed the authors to show that such fibrils then spread across connected brain regions. The authors said "this newly described transmission model may more faithfully recapitulate human Alzheimer's pathogenesis than the conventional transgenic mouse models of overexpressing mutant genes that develop aggregates. Exploring if this injection-transmission model is more appropriate for the progression of Alzheimer's, as well as Parkinson's, is another priority." Tau tangles play a role in frontotemporal dementia and other neurodegenerative disorders as well as Alzheimer's disease. The findings appeared in the Jan. 16, 2013, issue of the Journal of Neuroscience.

– Anette Breindl, Science Editor