Articles in 2012

Spinal and bulbar musclar atrophy (SBMA) is caused by expanded polyglutamine repeats in the androgen receptor, leading to motor neuron degeneration. Gen Sobue and his colleagues describe a molecular cascade whereby mutant androgen receptor upregulates CGRP in neuronal cells, promoting JNK activation and degeneration. The 5-HT1B/1D receptor agonist naratriptan, which is approved for the treatment of migraine, decreases CGRP expression and improves motor performance in a mouse model of SBMA, suggesting a novel therapeutic strategy for SBMA.

In congenital neutropenia, myeloid-lineage differentiation in response to the cytokine G-CSF is defective. Julia Skokowa et al. now show that an interplay among three proteins—the adapter proteins HCLS1 and HAX1 and the transcription factor LEF-1—is required for G-CSF–triggered granulocytic differentiation, and they provide evidence that this pathway is dysregulated in both congenital neutropenia and acute myeloid leukemia.

The authors identify LIFR as a breast cancer metastasis suppressor by showing how its loss promotes metastasis without substantial effect on primary tumor growth. This function of LIFR involves promoting the membrane localization of Scribble and enabling the cytoplasmic sequestration of Hippo pathway transducers, thus involving this signaling pathway in metastasis control. LIFR loss is also observed in human breast tumors, where it correlates with poor prognosis.

NRAS-driven melanomas have limited therapeutic options. Combining genetically engineered models and oncogenic signaling inhibitors with rational systems-biology approaches, the authors compare the effects of genetic extinction of NRAS to that of chemical pathway inhibition targeting downstream MEK. The differences provide actionable targets by revealing that NRAS signaling operates as a gated output and that MEK inhibition, although inducing apoptosis, is not able to achieve further inhibition of NRAS-induced outputs such as cell-cycle progression. A combination of MEK and CDK4 inhibitors provides a more complete inhibition of NRAS signaling and a more effective antitumor effect in vivo.

Although type I phosphatidylinositol 3-kinases (PI3Ks) are well studied signaling proteins, the functions of other PI3Ks are more enigmatic. Kazuaki Yoshioka et al. find that the type II PI3K-2α isoform regulates endosomal trafficking and cell signaling in endothelial cells. Angiogenic and vascular permeability responses are attenuated in mice lacking PI3K-2α, pointing to this enzyme as a potential target for treating vascular disease.

Obesity is often associated with mitochondrial dysfunction. What is not clear, however, is whether this is a cause or a consequence of the condition and its detrimental effects on metabolic health. Phil Scherer and colleagues now show that by manipulating a key protein involved in mitochondrial function specifically in adipocytes the mitochondria is crucial in maintaining proper lipid levels and whole-body insulin sensitivity.

Recurrent infections with respiratory syncytial virus (RSV) early in life increase susceptibility to asthma. Nandini Krishnamoorthy et al. show that RSV infection of young mice impairs maternally transferred tolerance to allergens. Regulatory T (T_reg) cells in infected mice have impaired suppressor function and adopt a T_H2-like phenotype.

Live attenuated SIV vaccines protect nonhuman primates from infection with pathogenic wild-type SIV, but the crucial mechanisms have not been clear. In this issue, Louis Picker and colleagues show that protection by live attenuated vaccines against intravenous SIV challenge in rhesus macaques is associated with SIV-specific T cell response in the lymph nodes, and not the blood, and persistent SIV replication in lymph node follicular T helper cells.

Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

Highly active antiretroviral therapy is crucial to controlling the progression of HIV infection. Therapy failure is often—but not always—attributed to resistance mutations in the HIV-1–encoded protein targets. Here Rosenbloom et al. use mathematical modeling to explain the distinct patterns of resistance found with different classes of antiretroviral drugs and predict specific single-pill combination therapies that might prevent resistance even in the setting of poor patient adherence.

Bacteria can be trapped by neutrophil extracellular traps (NETs) in vitro, but their relevance in vivo is uncertain, in part because NETs are thought to be released by dying neutrophils, thereby eliminating the other antimicrobial functions of these cells. Paul Kubes and his colleagues report in this issue that NET release need not kill neutrophils and that NETosis can by dynamically imaged in vivo.

Keisuke Ito et al. uncover a new pathway regulating hematopoietic stem cell maintenance and function. In this pathway, the promyelocytic leukemia protein (PML) regulates the activity of the PPAR-δ nuclear hormone receptor and, thereby, fatty acid oxidation, such that PPAR-δ activators have the potential of improving stem cell function. Intriguingly, this pathway controls the cell fate of dividing stem cells.

Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo. This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors.

T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells and suppresses T helper type 1 (T_H1) responses. Vijay Kuchroo and his colleagues show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds intracellularly to Tim-3 and represses its function. Bat3 knockdown suppresses the development of experimental autoimmune encephalomyelitis and induces an exhaustion-like phenotype in T cells.

In this issue, Walter et al. report the results of two clinical trials of a new therapeutic vaccine, IMA901, for the treatment of renal cell carcinoma (RCC). IMA901 consists of ten tumor-associated peptides identified as naturally presented T cell epitopes in RCC, and the authors show longer overall survival in subjects with immune responses to multiple vaccine peptides and identify serum and cellular biomarkers that may help predict overall survival in future studies of the vaccine.

Organ fibrosis often leads to end-stage organ failure, but the origin of key profibrotic cell types is still unclear. Lucie Peduto and her colleagues have used genetic lineage tracing and pharmacological ablation techniques to show that ADAM12⁺ perivascular cells are a key source of profibrotic cells in acute skin and muscle injury in the mouse. They also show that knockdown of ADAM12 expression is beneficial, suggesting a possible therapeutic target for the treatment of fibrosis.

The authors uncover a mechanism for the known antitumor effect exerted by neural precursor cells (NPCs). NPCs migrate into tumors in vivo and secrete endovanilloids, which act as agonists for TRPV1, their receptor expressed by glioma cells. TRPV1 activation causes ER stress and glioma cell death. The reported elevated concentration of TRPV1 in human gliomas and the antitumor effect of synthetic vanilloids suggest that this pathway could be a point of therapeutic intervention and that differential NPC activity, such as that modulated by age, could be a factor influencing brain tumorigenesis.

The glycocalyx is a layer of proteoglycans and complex carbohydrates that lines the endothelial cell surface in blood vessels. Schmidt et al. show that in mouse models of sepsis, lung inflammation and injury depend on glycocalyx degradation, which increases neutrophil access to endothelial adhesion molecules. The authors also provide data indicating the potential relevance of this mechanism of lung injury to humans with sepsis.

Although loss-of-function p53 alterations are widespread in many tumors, melanomas typically do not harbor TP53 mutations. This report uncovers upregulation of MDM4 as a frequent trait of melanomas that contributes to tumorigenesis by inactivating p53 signaling. MDM4 is required for growth and survival of melanoma cell lines, and compounds that can target MDM4 are effective against melanoma in vivo and against tumors resistant to BRAF-targeted therapy in vitro.

The authors identify Irf7 and associated interferon signaling as an important factor suppressing bone metastasis of breast cancers. Irf7 is lost in experimental metastasis and human bone metastastic tissue, and this fosters an immunosuppressive environment that facilitates metastasis. Manipulating this innate immune signaling pathway emerging from tumor cells by interferon administration had beneficial effects in mouse models by reducing bone metastasis and increasing survival time.