Articles in 2012

Tobias Eckle et al. describe a new regulatory circuit in the heart by which adenosine receptor signaling controls expression of the circadian protein Per2, which stabilizes the transcription factor Hif-1α, promotes glycolytic metabolism and has cardioprotective effects. Exposing mice to intense light was able to stabilize Per2 in the heart and reduce cardiac injury after myocardial ischemia.

Bone-marrow–derived stromal cells are known to protect against acute lung injury. Jahar Bhattacharya and colleagues now show that one way these cells offer such protection is to transfer their mitochondria to the injured lung epithelia to improve the bioenergetics of the recipient cells, thus probably allowing them to recover from injury more efficiently.

Age-related macular degeneration is a blinding disease associated with accumulation of aggregates called drusen in the retina. Now, Matthew Campbell and colleagues show that drusen can activate the inflammasome and that this activation protects against disease progression.

Ataxia-telangiectasia is a multifaceted disease that includes motor dysfunction caused by neuron death in the cerebellum. Now, Karl Herrup and colleagues report that ATM, the gene that is lost in the disease, keeps HDAC4 out of the nucleus and in the cytoplasm to maintain cerebellar neuron health.

Alternative splicing affects the function of many cardiac proteins, including that of the sarcomeric protein titin. Wei Guo et al. now show that the gene RBM20, previously identified as mutated in some individuals with dilated cardiomyopathy, is a splicing factor that regulates the alternative splicing of the gene encoding titin and many other key cardiac genes.

Engineered T cells expressing a tumor antigen specific T cell receptor (TCR) have shown promise for cancer immunotherapy. However, the introduced TCR chains can pair with the endogenous TCR chains in T cells, and in mice, these mismatched TCRs can cause a lethal autoimmune reaction. Provasi et al. now show that they can eliminate expression of the endogenous TCR chains using zinc finger nucleases and express only the desired exogenous TCR by lentiviral transduction. The resultant TCR-edited lymphocytes showed tumor specificity without the risk of off-target toxicity.

Alterations in commensal bacteria are associated with an increased risk of allergic disease. David Artis and his colleagues now report that commensal-derived signals influence basophil development and T_H2 cytokine–dependent allergic airway inflammation by suppressing serum IgE levels. Individuals with hyper IgE syndrome also have elevated circulating basophil numbers, suggesting a mechanistic link between commensal bacteria, B cell–mediated production of IgE and basophil hematopoiesis.

In human leprosy, a dendritic cell differentiation pathway that depends on interleukin-32 and is induced by NOD2 represents a novel mechanism of host defense against infection.

Intrinsic resistance to tyrosine kinase inhibitor (TKI) drugs is limiting the progress of targeted cancer therapies. The efficacy of TKIs relies on their inhibition of oncogenic signaling but also on the induction of apoptosis in cancer cells, driven by activation of pro-apoptotic BIM proteins. The authors identify a germline BIM polymorphism common in East Asian individuals that switches BIM splicing, eliminating the BH3 domain responsible for apoptosis induction. The polymorphism provides resistance to TKIs, such as BCR-ABL inhibitors in chronic myeloid leukemia and EGFR inhibitors in non–small-cell lung cancer samples, and drug sensitivity can be reinstated by addition of BH3-mimetic drugs. The polymorphism predicts treatment responses and outcome in East Asian patients with leukemia and lung cancer and could provide useful guidance for therapeutic implementation.

Leptin and BDNF are two protein cytokines known to inhibit food intake. Baoji Xu and colleagues have now shown that leptin-mediated inhibition of food intake is dependent on leptin binding to one set of hypothalamic neurons, which results in neuronal activation of other hypothalamic neurons to increase the dendritic expression of BDNF in those targeted neurons. These results show a new functional link between these two anorexigenic cytokines and how leptin signaling is propagated to regulate food intake.

HIV infection is often associated with severe nephropathy, including renal fibrosis. John He and his colleagues have used a systems biology approach in a mouse model of HIV infection to identify the key factors involved in this process, thus identifying the kinase HIPK2 as one such factor. They also show that HIPK2 genetic deletion prevented renal fibrosis in two other mouse models, suggesting this kinase has a general role in the fibrotic process.

Hepatic precursor cells (HPCs) are known to be bipotent and to give rise to both new hepatocytes and cholangiocytes upon acute liver injury. Stuart J. Forbes and his colleagues now show that interactions of HPCs with local macrophages and myofibroblasts potentiate Wnt and Notch signaling, respectively, to determine fate specification of the HPCs. Together, these mechanisms help determine proper organ regeneration after liver injury.

The authors uncover a role for the tyrosine phosphatase SHP2 in the propagation and maintenance of breast cancer tumor initiating cells. This role of SHP2 contributes to the growth and metastasis of tumors in vivo and is mediated by a newly uncovered downstream pathway that, through regulation of ERK, modulates the activity of transcription factors such as ZEB1 and Myc, also affecting microRNAs such as let-7. A genetic signature of SHP2 activation is indicative of increased aggressiveness in human breast cancers.

IL-17 is associated with asthma, and T_HH17 cells are found in the airways of individuals with asthma. Dean Sheppard and his colleagues now report that IL-17A (but not IL-17F) directly enhances contractile responses in airway smooth muscle cells. Mice lacking T_H17 cells in the lungs exhibit reduced airway hyper-responsiveness in response to allergen challenge.

In 2004, a team led by Jonathan Tilly reported that mice contained oogonial stem cells (OSCs), suggesting that females may be able to generate new oocytes in adulthood—a concept that was, and still is, quite controversial even though those findings have since been replicated by others. In a new report, Tilly and colleagues now perfect the purification of mouse OSCs and, using this technique, they show that similar cells exist in women of reproductive age. They also show that the mouse and human OSCs are able to give rise to oocytes in vivo (in the case of the human cells after xenotransplantation into NOD-SCID mice), while also showing that the mouse OSCs can give rise to embryos after in vitro fertilization.

CD8⁺ T cells primed in the absence of CD4⁺ T cell help fail to develop a robust memory cell response. Zloza et al. now report that these CD4-unhelped CD8⁺ T cells can be rescued by activating their cell surface receptor NKG2D, which restores CD8⁺ T cell expansion and cytolytic activity during a recall response and protection in a mouse model of influenza infection.

TGF-β signaling is commonly aberrantly activated in gliomas and other tumors and can exert a pro-oncogenic function. The authors identify a new mechanism for upregulation of TGF-β signaling in cancer. The deubiquitinase USP15 is shown to be able to bind the TGF-β receptor complex, counteract its degradation and potentiate its stimulation of downstream mediators. USP15 is amplified in human glioblastoma and could represent a therapeutic target, as its downregulation impairs the growth of glioblastoma cells in vivo.

The insulin signaling pathway regulating glucose homeostasis that has been well accepted is insulin-to-insulin receptor-to-IRS proteins-to-PI3K-to-Akt-to-Foxo1—a pathway that does not respond properly in states of insulin resistance, including type 2 diabetes. In a new study from Morris Birnbaum and colleagues, an alternative insulin signaling pathway has been uncovered, as mice with liver-specific deletion of Akt and Foxo1 still respond normally to nutritional cues and properly regulate glucose metabolism. Although the exact nature of this alternative pathway needs to be identified, the results should open many new avenues of exploration in the field of type 2 diabetes.

In a new study, Yasuhiro Kobayashi and his colleagues show that noncanonical Wnt signaling regulates balanced osteoblast-induced osteoclastogenesis during normal physiology and that this pathway is perturbed in pathophysiological states, such as rheumatoid arthritis. These results explain further how osteoblasts cross-talk with preosteoclasts to ensure matched bone resorption with bone formation during skeletal homeostasis in the adult and also suggest a new target to treat arthritis.

BMP7 has been previously shown to protect against renal fibrosis. Raghu Kalluri and his colleagues have now identified activin-like kinase 3 (Alk3) as the key co-receptor for BMP7 in the kidney and have identified an orally available, small-peptide agonist of Alk3 that reduces established fibrosis in five animal models of kidney injury.