Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.

http://science.sciencemag.org/content/sci/306/5695/457.full.pdf

Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.

MicroRNAs in cancer.

2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.

Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.

MicroRNAs (miRNAs) are a class of posttranscriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. There are currently over 10,000 miRNAs that have been identified in a range of species including metazoa, mycetozoa, viridiplantae, and viruses, of which 940, to date, are found in humans. It is estimated that more than 60% of human protein-coding genes harbor miRNA target sites in their 3′ untranslated region and, thus, are potentially regulated by these molecules in health and disease. This review will first briefly describe the discovery, structure, and mode of function of miRNAs in mammalian cells, before elaborating on their roles and significance during development and pathogenesis in the various mammalian organs, while attempting to reconcile their functions with our existing knowledge of their targets. Finally, we will summarize some of the advances made in utilizing miRNAs in therapeutics.

/pdf/micrornas-in-development-and-disease-472gt45lvo.pdf

MicroRNAs in development and disease.

Excitotoxicity and stroke: identifying novel targets for neuroprotection.

Identification of the critical features of a small peptide inhibitor of JNK activity.

Venoms have evolved over millions of years into potent cocktails of bioactive peptides and proteins. These compounds can be of great value to the pharmaceutical industry for numerous clinical applications. In this study, a novel proteomic - bioinformatic approach was utilised, where chromatography followed by gel electrophoresis was utilised to separate the venom peptides/proteins of Heterometrus longimanus (Asian black scorpion). Purified peptides were analysed by tandem mass spectrometry, de novo sequenced and then homology matched against known peptides in the Swiss-Prot protein database. Numerous potentially biologically active peptide matches were discovered, and a simple scoring system applied to putatively assign functions to the peptides. As a validation of this approach, the functional composition of the experimentally derived proteome is similar to that of other scorpions, and contains a potent mix of toxins, antimicrobials and ionic channel inhibitors.

Proteomic analysis of the venom of Heterometrus longimanus (Asian black scorpion).

miR-331-3p Regulates ERBB-2 Expression and Androgen Receptor Signaling in Prostate Cancer

A cell delivery system is increasing in use in many areas of cell and molecular biology and bio-medicine. This system is based on a number of naturally occurring protein motifs and/or sequences which show the remarkable ability to rapidly cross the mammalian cell membrane without compromising its structure or function. These so-called Protein Transduction Domains (PTDs) offer unprecedented advantages for intracellular delivery. These advantages include, but are not limited to, their applicability to all cell types (no cell type has yet been described which is not transduced by these PTDs), and the range of cargoes that can be transduced (including peptides, small proteins, full-length enzymes, DNA oligomers, peptide-nucleic acid oligomers, liposomes, and magnetic nanoparticles). Furthermore, the PTDs have been demonstrated to be suitable for in vivo delivery including delivery across the blood brain barrier, and have been shown to cross the plasma membrane rapidly and enter the cytoplasm and nuclear regions of the cell. In this review, the general properties of the most commonly used PTDs are described. The strategies currently being undertaken also highlight that improvements in membrane transduction are possible despite our lack of understanding of the exact biochemical and/or physical mechanisms of transduction. Recent examples of the range of potential applications are also discussed.

Tulene S. Kendrick

Papers

Identification of the critical features of a small peptide inhibitor of JNK activity.

Proteomic analysis of the venom of Heterometrus longimanus (Asian black scorpion).

miR-331-3p Regulates ERBB-2 Expression and Androgen Receptor Signaling in Prostate Cancer

Taking the cell by stealth or storm? Protein transduction domains (PTDs) as versatile vectors for delivery.

Erythroid defects in TRα−/− mice