Articles in 2010

Jian-Xun Wang et al. show that mitochondrial fission, which occurs during cell death, is regulated in cardiomyocytes by the microRNA miR-499 through a mechanism involving the phosphatase calcineurin and its substrate Drp1. Overexpression of miR-499 was able to reduce mitochondrial fission and apoptosis in the hearts of mice or rats injured by ischemia-reperfusion and to improve heart function, suggesting new therapeutic approaches for myocardial injury.

The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor.

Yujin Zhang et al. discovered that the concentration of adenosine in the blood is increased both in a mouse model of sickle cell disease and in humans with this disease. Adenosine seems to have a pathological role in this disease, as it induced sickling of human erythrocytes through a mechanism involving activation of the A_2B adenosine receptor. Treatment of the mouse model of sickle cell disease with an agent to lower adenosine levels or with an A_2B adenosine receptor antagonist had beneficial effects, pointing to new therapeutic strategies for this disease.

Histidine decarboxylase (Hdc) is required for the endogenous production of histamine, but its role in tumorigenesis is unclear. Yang et al. now report that Hdc-deficient mice develop more tumors in models of chemically induced carcinogenesis, associated with an increased recruitment of immature myeloid cells to the tumors and higher amounts of interleukin-6. The authors further show that Hdc deficiency inhibits myeloid cell maturation and that exogenous histamine promotes monocyte differentiation and suppresses tumor growth.

A subset of series B adenoviruses binds epithelial cells via a previously unknown receptor. Wang et al. now identify this receptor as desmoglein-2 (DSG-2), which has a role in intercellular adhesion. Binding of group B Ad3 to DSG-2 triggered an epithelial to mesenchymal transition, opened intercellular junctions and increased access to junction-localized proteins, which together may contribute to the spread of these viruses though epithelial tissues.

Expression of miR-124, a microglial microRNA, reduces disease in a mouse model of multiple sclerosis by inhibiting the transcription factor C/EBP-α and its downstream target PU.1.

One complication arising from gastrointestinal surgery is ileus, in which local manipulation of the intestine leads to dysmotility and paralysis of the entire intestine. Christian Kurts and his colleagues find that after surgery T helper type 1 memory cells are activated by intestinal dendritic cells via interleukin-12, and migration of memory T cells through the portal vein induces paralysis of unmanipulated sites. Inhibition of interleukin-12 or prevention of lymphocyte egress with FTY720 prevents ileus and suggests new targets for therapeutic intervention.

Physiological Stat3 signaling is temporally restricted. In cancer, Stat3 activity is often persistently elevated and fosters progression through its effects on tumor cells and their microenvironment. This report identifies the reciprocal positive regulation of S1PR1 and Stat3 in tumors as a mechanism by which tumor cells and their environment crosstalk to maintain Stat3 activity. This persistent loop is required for tumor progression and metastasis and could be a potential therapeutic target to block oncogenic Stat3 signaling.

Under certain conditions, endothelial cells can transform into mesenchymal cell types, a process known as endothelial-to-mesenchymal transition. Damian Medici et al. now provide evidence that this type of transition contributes to the generation of the ossified lesions of individuals with fibrodysplasia ossificans progressiva. Experiments in mice and in cultured endothelial cells indicate that activation of the ALK2 receptor in endothelial cells endows them with the ability to differentiate into a number of cell types.

The transition from androgen-dependent to castration-resistant prostate cancer is a lethal event. N-cadherin seems to be a major cause underlying this transition, and targeting this adhesion molecule may have positive clinical benefit.

Autophagy is often believed to be elevated in disease, contributing to pathogenesis. Paolo Bonaldo and his colleagues now show that it is actually too little autophagy that occurs in some forms of muscular dystrophy, resulting in the continued presence of defective mitochondria and thus myofiber degeneration. They also show that increasing autophagy via dietary or pharmacological means can ameliorate muscle pathology in a mouse model of human muscular dystrophy.

In asthmatic individuals, a small subset of CD4⁺ T cells express the chemokine receptor CX3CR1, whose ligand is CX3CL1. In this issue, Mionnet et al. report that this chemokine-receptor pair is important in experimental asthma, conferring a survival advantage on CX3CR1-expressing CD4⁺ T cells, and show that blocking CX3CR1 signaling has therapeutic benefit in mice.

G protein-coupled receptor (GPCR)-mediated increases in intracellular calcium generally lead to constriction of airway smooth muscle. Deshpande et al. find that bitter taste receptors, another class of GPCRs, are also expressed on airway smooth muscle cells and, once activated, induce a localized increase in intracellular calcium. Paradoxically, this induces relaxation of airway smooth muscle cells via activation of BK_Ca channels. These ligands also relax airways in a mouse model of asthma, suggesting they can be used in conjunction with β-adrenergic receptor agonists to treat obstructive lung disease.

The oncogenic activation of TLX transcription factors demarcates a specific molecular subtype of T cell acute lymphoblastic leukemia (T-ALL). This study identifies aneuploidy induction as a molecular mechanism by which TLX1 transforms T cell progenitors and reveals new TLX1 transcriptional targets, including Bcl11b, a crucial factor in T cell progenitor differentiation and survival, and Chek1, a mitotic checkpoint regulator. The findings delineate the role of TLX1 in T-ALL initiation and maintenance.

The characterization of miR-380-5p–driven p53 repression provides a new mechanism for downmodulation of stress-induced antiproliferative responses in wild-type p53 contexts, including embryonic stem cells and neuroblastoma tumors. miR-380-5p potentiates Ras-induced mammary gland tumorigenesis and is frequently elevated in human neuroblastomas. miR-380-5p inactivation induces tumor cell death and shows therapeutic efficacy in orthotopic neuroblastoma models.

Mutations in ATP8b1 are found in certain individuals susceptible to pneumonia. Ray et al. now report that bacterial pneumonia is associated with elevated levels of the phospholipid cardiolipin in airway fluids, that ATP8b1 is a cardiolipin importer and that excessive cardiolipin in the lung contributes to impaired lung function. The findings suggest that ATP8b1 might be a new therapeutic target for the treatment of pneumonia.

A C-type lectin receptor, SIGNR-1, helps dendritic cells in the gut induce oral tolerance. Sugar-modified antigens might therefore be used to induce oral tolerance to food-induced anaphylaxis.

Pathologically altered stromas are a common contributing factor to cancer progression and fibrogenesis. This report uncovers the role of LOXL2 in the creation and maintenance of the pathological microenvironment of human cancers and fibrotic diseases and presents the development of a LOXL2-specific antibody that shows therapeutic activity in tumor as well as lung and liver fibrosis models.

Thyroid hormones are well known to regulate whole-body energy metabolism, which was believed to occur as a direct effect on individual cells in the periphery. But Antonio Vidal-Puig and his colleagues now show that these thyroid hormone effects on energy regulation are actually indirect, as they regulate AMPK activity in the hypothalamus and thus central signaling to brown adipose tissue in the periphery.

Neutrophils release the serine proteases neutrophil elastase and cathepsin G, which have microbicidal activity and thereby contribute to the innate immune response. Steffen Massberg et al. now show that these neutrophil serine proteases, in association with extracellular nucleosomes, can also promote coagulation and thrombosis within large blood vessels. In a mouse model of systemic bacterial infection, these proteases spurred intravascular coagulation in the microcirculation of the liver, limiting bacterial tissue invasion. These findings point to a role for thrombosis in antimicrobial defense.