Emerging roles for WNK kinases in cancer

The subfamily of WNK protein kinases is composed of four human genes and is characterised by a typical sequence variation within the conserved catalytic domain. Although most research has focussed on the role of WNK1, WNK3 and WNK4 in regulating different ion transporters in both the kidney and extrarenal tissues, there is growing evidence for additional roles of WNK kinases in various signalling cascades related to cancer. Here, we review the connection between WNK kinases and tumorigenesis and describe existing experimental evidence as well as potential new links to major aspects of tumour biology. In particular, we discuss their role in G1/S cell cycle progression, metabolic tumour cell adaptation, evasion of apoptosis and metastasis.     

Emerging roles of immunoproteasomes beyond MHC class I antigen processing

The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8(+) T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events militates against the view that its role is limited to MHC class I presentation. In support of this concept, the recent use of genetic models deficient for β1i/LMP2, β2i/MECL-1, or β5i/LMP7 has uncovered unanticipated functions for IP in innate immunity and non-immune processes. Herein, we review recent data in an attempt to clarify the role of IP beyond MHC class I epitope presentation with emphasis on its involvement in the regulation of protein homeostasis, cell proliferation, and cytokine gene expression.     

Emerging roles of the oxysterol-binding protein family in metabolism, transport, and signaling

OSBP (oxysterol-binding protein) and ORPs (OSBP-related proteins) constitute an enigmatic eukaryotic protein family that is united by a signature domain that binds oxysterols, sterols, and possibly other hydrophobic ligands. The human genome contains 12 OSBP/ORP family members genes, while that of the budding yeast Saccharomyces cerevisiae encodes seven OSBP homologues (Osh). Of these, Osh4 (also referred to as Kes1) has been the most widely studied to date. Recently, three-dimensional crystal structures of Osh4 with and without sterols bound within the core of the protein were determined. The core consists of 19 anti-parallel β-sheets that form a near-complete β-barrel. Recent work has suggested that Osh proteins facilitate the non-vesicular transport of sterols in vivo and in vitro, while other evidence supports a role for Osh proteins in the regulation of vesicular transport and lipid metabolism.This article will review recent advances in the study of ORP/Osh proteins and will discuss future research issues regarding the ORP/Osh family. Received 17 July 2007; received after revision 14 August 2007; accepted 12 September 2007     

Emerging knowledge of regulatory roles of <Emphasis Type="SmallCaps">d-</Emphasis>amino acids in bacteria

The d-enantiomers of amino acids have been thought to have relatively minor functions in biological processes. While l-amino acids clearly predominate in nature, d-amino acids are sometimes found in proteins that are not synthesized by ribosomes, and d-Ala and d-Glu are routinely found in the peptidoglycan cell wall of bacteria. Here, we review recent findings showing that d-amino acids have previously unappreciated regulatory roles in the bacterial kingdom. Many diverse bacterial phyla synthesize and release d-amino acids, including d-Met and d-Leu, which were not previously known to be made. These noncanonical d-amino acids regulate cell wall remodeling in stationary phase and cause biofilm dispersal in aging bacterial communities. Elucidating the mechanisms by which d-amino acids govern cell wall remodeling and biofilm disassembly will undoubtedly reveal new paradigms for understanding how extracytoplasmic processes are regulated as well as lead to development of novel therapeutics.     

The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: implications for schizophrenia and addiction

Cannabinoids represent one of the most widely used hallucinogenic drugs and induce profound alterations in sensory perception and emotional processing. Similarly, the dopamine (DA) neurotransmitter system is critical for the central processing of emotion and motivation. Functional disturbances in either of these neurotransmitter systems are well-established correlates of the psychopathological symptoms and behavioral manifestations observed in addiction and schizophrenia. Increasing evidence from the anatomical, pharmacological and behavioral neuroscience fields points to complex functional interactions between these receptor systems at the anatomical, pharmacological and neural systems levels. An important question relates to whether these systems act in an orchestrated manner to produce the emotional processing and sensory perception deficits underlying addiction and schizophrenia. This review describes evidence for functional neural interactions between cannabinoid and DA receptor systems and how disturbances in this neural circuitry may underlie the aberrant emotional learning and processing observed in disorders such as addiction and schizophrenia. Received 20 January 2006; received after revision 14 March 2006; accepted 29 March 2006     

Emerging Role of MicroRNAs in mTOR Signaling

Mechanistic target of rapamycin (mTOR) is a conserved serine/threonine kinase that plays a critical role in the control of cellular growth and metabolism. Hyperactivation of mTOR pathway is common in human cancers, driving uncontrolled proliferation. MicroRNA (miRNA) is a class of short noncoding RNAs that regulate the expression of a wide variety of genes. Deregulation of miRNAs is a hallmark of cancer. Recent studies have revealed interplays between miRNAs and the mTOR pathway during cancer development. Such interactions appear to provide a fine-tuning of various cellular functions and contribute qualitatively to the behavior of cancer. Here we provide an overview of current knowledge regarding the reciprocal relationship between miRNAs and mTOR pathway: regulation of mTOR signaling by miRNAs and control of miRNA biogenesis by mTOR. Further research in this area may prove important for the diagnosis and therapy of human cancer.     

Specificity of the macrophage reaction in vitro

Résumé Les macrophages de cobayes immunisés provoquent in vitro l'adhérence des hématies utilisées comme antigènes, selon une spécificité d'éspèce et non de groupe. Les sérums humains s'adsorbent in vitro sur les macrophages de cobayes immunisés par ces sérums, indépendemment du groupe (mais non sur des macrophages de cobayes normaux) causant l'adhérence et la phagocytose des hématies correspondantes. Les hématies adhérant aux macrophages sont hémolysées en présence du complément.     

Antithetic roles of proteoglycans in cancer

Proteoglycans (PGs), a family of complex post-translationally sculptured macromolecules, are fundamental regulators of most normal and aberrant cellular functions. The unparalleled structural–functional diversity of PGs endows them with the ability to serve as critical mediators of the tumor cells’ interaction with the host microenvironment, while directly contributing to the organization and dynamic remodeling of this milieu. Despite their indisputable importance during embryonic development and in the adult organism, and their frequent dysregulation in tumor lesions, their precise involvement in tumorigenesis awaits a more decisive demonstration. Particularly challenging is to ascertain to what extent selected PGs may catalyze tumor progression and to what extent they may inhibit it, implying antithetic functions of individual PGs. Integrated efforts are needed to consolidate the routine use of PGs in the clinical monitoring of cancer patients and to broaden the exploitation of these macromolecules as therapeutic targets. Several PGs have the required attributes to be contemplated as effective antigens for immunotherapeutic approaches, while the tangible results obtained in recent clinical trials targeting the NG2/CSPG4 transmembrane PG urge further development of PG-based cancer treatment modalities.     

The role of proteolytic processing in the morphogenesis of virus particles

Proteinases are encoded by many RNA viruses, all retroviruses and several DNA viruses. They play essential roles at various stages in viral replication, including the coordinated assembly and maturation of virions. Most of these enzymes belong to one of three (Ser, Cys or Asp) of the four major classes of proteinases, and have highly substrate-selective and cleavage specific activities. They can be thought of as playing one of two general roles in viral morphogenesis. Structural proteins are encoded by retroviruses and many RNA viruses as part of large polyproteins. Their proteolytic release is a prerequisite to particle assembly; consequent structural rearrangement of the capsid domains serves to regulate and direct association and assembly of capsid subunits. The second general role of proteolysis is in assembly-dependent maturation of virus particles, which is accompanied by the acquisition of infectivity.     

Heterogeneity of macrophage cytophilic antibodies in immunized mice

Résumé Des souris immunisés avec des globules rouges de mouton dans l'adjuvant de Freund produisent deux types de facteurs cytophiles pour macrophages. L'un s'attache aux macrophages trypsinisées et se trouve parmi les immunoglobulines. L'autre ne s'attache pas aux macrophages trypsinisées et se rencontre dans une fraction de sérum contenant de l'albumine et de la globuline-₁.

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Supported by grants from the Australian Research Grants Committee, the National Health and Medical Research Council of Australia and the Postgraduate Medical Foundation, University of Sydney.     

A non-dialyzable inhibitor of proteolytic activity in soluble extracts ofEscherichia coli

Résumé Nous avons observé l'inhibition de l'activité tryptique et chymotryptique par extraits d'Escherichia coli. L'inhibition n'est pas détruit par chauffage et par dialyse.