Biochemical Society transactions最新文献

Decades of research into the Hippo signaling pathway have greatly advanced our understanding of its roles in organ growth, tissue regeneration, and tumorigenesis. The Hippo pathway is frequently dysregulated in human cancers and is recognized as a prominent cancer signaling pathway. Hence, the Hippo pathway represents an ideal molecular target for cancer therapies. This review will highlight recent advancements in targeting the Hippo pathway for cancer treatment and discuss the potential opportunities for developing new therapeutic modalities.

The growth and development of metazoan organisms is dependent upon a co-ordinated programme of cellular proliferation and differentiation, from the initial formation of the zygote through to maintenance of mature organs in adult organisms. Early studies of proliferation of ex vivo cultures and unicellular eukaryotes described a cyclic nature of cell division characterised by periods of DNA synthesis (S-phase) and segregation of newly synthesized chromosomes (M-phase) interspersed by seeming inactivity, the gap phases, G1 and G2. We now know that G1 and G2 play critical roles in regulating the cell cycle, including monitoring of favourable environmental conditions to facilitate cell division, and ensuring genomic integrity prior to DNA replication and nuclear division. M-phase is usually followed by the physical separation of nascent daughters, termed cytokinesis. These phases where G1 leads to S phase, followed by G2 prior to M phase and the subsequent cytokinesis to produce two daughters, both identical in genomic composition and cellular morphology are what might be termed an archetypal cell division. Studies of development of many different organs in different species have demonstrated that this stereotypical cell cycle is often subverted to produce specific developmental outcomes, and examples from over 100 years of analysis of the development of Drosophila melanogaster have uncovered many different modes of cell division within this one species.

Translational control is crucial for well-balanced cellular function and viability of organisms. Different mechanisms have evolved to up- and down-regulate protein synthesis, including 3' untranslated region (UTR)-mediated translation repression. RNA binding proteins or microRNAs interact with regulatory sequence elements located in the 3' UTR and interfere most often with the rate-limiting initiation step of translation. Dysregulation of post-transcriptional gene expression leads to various kinds of diseases, emphasizing the significance of understanding the mechanisms of these processes. So far, only limited mechanistic details about kinetics and dynamics of translation regulation are understood. This mini-review focuses on 3' UTR-mediated translational regulation mechanisms and demonstrates the potential of using single-molecule fluorescence-microscopy for kinetic and dynamic studies of translation regulation in vivo and in vitro.

Rab GTPase proteins have been extensively studied for their roles in regulating vesicle and organelle dynamics. Among the ∼60 subtypes in mammalian cells, several Rabs have been reported to play crucial roles in osteoclast biogenesis and function. In this review, we aim to provide an update on recently described Rab GTPases, Rab11, Rab32, Rab44, and Rab38, as well as Rab7, Rab3D and Rab27A in osteoclast formation and function.

Integral polytopic α-helical membrane transporters and aquaporins move and distribute various molecules and dispose of or compartmentalize harmful elements that gather in living cells. The view shaped nearly 25 years ago states that integrating these proteins into cellular membranes can be considered a two-stage process, with hydrophobic core folding into α-helices across membranes to form functional entities (Popot and Engelman, 1990; Biochemistry29, 4031-4037). Since then, a large body of evidence cemented the roles of structural properties of membrane proteins and bilayer solvent components in forming functional assemblies. This mini-review updates our understanding of multifaced factors, which underlie transporters integration and oligomerization, focusing on water-permeating aquaporins. This work also elaborates on how individual monomers of bacterial and mammalian aquaporin tetramers, interact with each other, and how tetramers form contacts with lipids after being embedded in lipid bilayers of known composition, which mimics bacterial and mammalian membranes. Although this mini-review describes findings acquired using current methods, the view is open to how to extend this knowledge through, e.g. single-molecule-based and in situ cryogenic-electron tomography techniques. These and other methods could unravel the sources of entropy for membrane protein assemblies and pathways underlying integration, folding, oligomerization and quaternary structure formation with binding partners. We could expect that these exceedingly interdisciplinary approaches will form the basis for creating optimized transport systems, which could inspire bioengineering to develop a sustainable and healthy society.

Staphylococcus aureus is a highly significant pathogen with several well studied and defined virulence factors. However, the metabolic pathways that are required to facilitate infection are not well described. Previous data have documented that S. aureus requires glucose catabolism during initial stages of infection. Therefore, certain nutrients whose biosynthetic pathway is under carbon catabolite repression and CcpA, including arginine, must be acquired from the host. However, even though S. aureus encodes pathways to synthesize arginine, biosynthesis of arginine is repressed even in the absence of glucose. Why is S. aureus a functional arginine auxotroph? This review discusses recently described regulatory mechanisms that are linked to repression of arginine biosynthesis using either proline or glutamate as substrates. In addition, recent studies are discussed that shed insight into the ultimate mechanisms linking arginine auxotrophy and infection persistence.

Reverse micelles (RMs) have emerged as useful tools for the study of membrane associated proteins. With a nanoscale water core surrounded by surfactant and solubilized in a non-polar solvent, RMs stand apart as a unique membrane model. While RMs have been utilized as tools to investigate the physical properties of membranes and their associated water, RMs also effectively house membrane associated proteins for a variety of studies. High-resolution protein NMR revealed a need for development of improved RM formulations, which greatly enhanced the use of RMs for aqueous proteins. Protein-optimized RM formulations enabled encapsulation of challenging membrane associated protein types, including lipidated proteins, transmembrane proteins, and peripheral membrane proteins. Improvements in biological accuracy of RMs using phospholipid-based surfactants has advanced their utility as a membrane mimetic even further, better matching the chemistry of the most common cellular membrane lipids. Natural lipid extracts may also be used to construct RMs and house proteins, resulting in a membrane model that better represents the complexity of biological membranes. Recent applications in high-resolution investigations of protein-membrane interactions and inhibitor design of membrane associated proteins have demonstrated the usefulness of these systems in addressing this difficult category of protein. Further developments of RMs as membrane models will enhance the breadth of investigations facilitated by these systems and will enhance their use in biophysical, structural, and drug discovery pursuits of membrane associated proteins. In this review, we present the development of RMs as membrane models and their application to structural and biophysical study of membrane proteins.

Hypoxia Inducible transcription Factors (HIFs) are central to the metazoan oxygen-sensing response. Under low oxygen conditions (hypoxia), HIFs are stabilised and govern an adaptive transcriptional programme to cope with prolonged oxygen starvation. However, when oxygen is present, HIFs are continuously degraded by the proteasome in a process involving prolyl hydroxylation and subsequent ubiquitination by the Von Hippel Lindau (VHL) E3 ligase. The essential nature of VHL in the HIF response is well established but the role of other enzymes involved in ubiquitination is less clear. Deubiquitinating enzymes (DUBs) counteract ubiquitination and provide an important regulatory aspect to many signalling pathways involving ubiquitination. In this review, we look at the complex network of ubiquitination and deubiquitination in controlling HIF signalling in normal and low oxygen tensions. We discuss the relative importance of DUBs in opposing VHL, and explore roles of DUBs more broadly in hypoxia, in both VHL and HIF independent contexts. We also consider the catalytic and non-catalytic roles of DUBs, and elaborate on the potential benefits and challenges of inhibiting these enzymes for therapeutic use.

Cytokinins are one of the main groups of plant hormones that regulate growth and development of plants. Cytokinin oxidase/dehydrogenase (CKX) is an enzyme that rapidly and irreversibly degrades cytokinins and thus directly affects their concentration and physiological effect. Genetically modified plants with reduced CKX activity in the shoot, i.e. with a higher concentration of cytokinins, showed e.g. increased tolerance to drought stress, formed larger inflorescences and had higher grain yield. For these reasons, chemical compounds capable of inhibiting the CKX activity (CKX inhibitors) were sought. First, they were identified among strong synthetic cytokinins, but their inhibitory activity was low. The trend has been to develop potent CKX inhibitors with minimal intrinsic cytokinin activity in the hope of avoiding the negative effect of cytokinins on root growth. Cloning CKX, production of key recombinant enzymes from Arabidopsis (AtCKX2) and maize (ZmCKX1 and ZmCKX4a), development of screening bioassays and progress in X-ray crystallography and synthetic organic chemistry led to extensive progress in the development of these compounds. Currently, the most suitable CKX inhibitors are seeking their application in research and the commercial sphere in two main areas - plant tissue cultures and agriculture. The key milestones that preceded it are summarized in this review.

Skeletal muscle cells (myofibers) require multiple nuclei to support a cytoplasmic volume that is larger than other mononuclear cell types. It is dogmatic that mammalian resident myonuclei rely on stem cells (specifically satellite cells) for adding new DNA to muscle fibers to facilitate cytoplasmic expansion that occurs during muscle growth. In this review, we discuss the relationship between cell size and supporting genetic material. We present evidence that myonuclei may undergo DNA synthesis as a strategy to increase genetic material in myofibers independent from satellite cells. We then describe the details of our experiments that demonstrated that mammalian myonuclei can replicate DNA in vivo. Finally, we present our findings in the context of expanding knowledge about myonuclear heterogeneity, myonuclear mobility and shape. We also address why myonuclear replication is potentially important and provide future directions for remaining unknowns. Myonuclear DNA replication, coupled with new discoveries about myonuclear transcription, morphology, and behavior in response to stress, may provide opportunities to leverage previously unappreciated skeletal muscle biological processes for therapeutic targets that support muscle mass, function, and plasticity.