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The short pre-M1 helix within the S1–M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation. [ABSTRACT FROM AUTHOR]

Several studies emphasized the function of the thyroid hormones in stem cell biology. These hormones act through the nuclear hormone receptor TRs, which are T3-modulated transcription factors. Pioneer work on T3-dependent amphibian metamorphosis showed that the crosstalk between the epithelium and the underlying mesenchyme is absolutely required for intestinal maturation and stem cell emergence. With the recent advances of powerful animal models and 3D-organoid cultures, similar findings have now begun to be described in mammals, where the action of T3 and TRα1 control physiological and cancer-related stem cell biology. In this review, we have summarized recent findings on the multiple functions of T3 and TRα1 in intestinal epithelium stem cells, cancer stem cells and their niche. In particular, we have highlighted the regulation of metabolic functions directly linked to normal and/or cancer stem cell biology. These findings help explain other possible mechanisms by which TRα1 controls stem cell biology, beyond the more classical Wnt and Notch signaling pathways. [ABSTRACT FROM AUTHOR]

Liver regeneration (LR) capacity in vertebrates developed through natural selection over a hundred million years of evolution. To maintain homeostasis or recover from various injuries, liver cells must regenerate; this process includes the renewal of parenchymal and nonparenchymal cells as well as the formation of liver structures. The cellular origin of newly grown tissue is one of the critical questions in this area and has been a subject of prolonged debate. The regenerative tissue may derive from either hepatocyte self-duplication or liver stem/progenitor cells (LSPCs). Recently, hepatocyte subpopulations and cholangiocytes were also described as important founder cells. The niche that triggers the proliferation of hepatocytes and the differentiation of LSPCs has been extensively studied. Meanwhile, in vitro culture systems for liver founder cells and organoids have been developed rapidly for mechanistic studies and potential therapeutic purposes. This review summarizes the cellular sources and niches that give rise to renewed hepatocytes during LR, and it also describes in vitro culture studies of those founder cells for future applications, as well as current reports for stem cell-based therapies for liver diseases. [ABSTRACT FROM AUTHOR]

Daily fluctuations in animal physiology, known as circadian rhythms, are orchestrated by a conserved molecular timekeeper, known as the circadian clock. The circadian clock forms a transcription–translation feedback loop that has emerged as a central biological regulator of many 24-h processes. Early studies of the intestine discovered that many digestive functions have a daily rhythm and that intestinal cell production was similarly time-dependent. As genetic methods in model organisms have become available, it has become apparent that the circadian clock regulates many basic cellular functions, including growth, proliferation, and differentiation, as well as cell signalling and stem cell self-renewal. Recent connections between circadian rhythms and immune system function, and between circadian rhythms and microbiome dynamics, have also been revealed in the intestine. These processes are highly relevant in understanding intestinal stem cell biology. Here we describe the circadian clock regulation of intestinal stem cells primarily in two model organisms: Drosophila melanogaster and mice. Like all cells in the body, intestinal stem cells are subject to circadian timing, and both cell-intrinsic and cell-extrinsic circadian processes contribute to their function. [ABSTRACT FROM AUTHOR]

Mammalian spermatogenesis is a highly complex multi-step process sustained by a population of mitotic germ cells with self-renewal potential known as spermatogonial stem cells (SSCs). The maintenance and regulation of SSC function are strictly dependent on a supportive niche that is composed of multiple cell types. A detailed appreciation of the molecular mechanisms underpinning SSC activity and fate is of fundamental importance for spermatogenesis and male fertility. However, different models of SSC identity and spermatogonial hierarchy have been proposed and recent studies indicate that cell populations supporting steady-state germline maintenance and regeneration following damage are distinct. Importantly, dynamic changes in niche properties may underlie the fate plasticity of spermatogonia evident during testis regeneration. While formation of spermatogenic colonies in germ-cell-depleted testis upon transplantation is a standard assay for SSCs, differentiation-primed spermatogonial fractions have transplantation potential and this assay provides readout of regenerative rather than steady-state stem cell capacity. The characterisation of spermatogonial populations with regenerative capacity is essential for the development of clinical applications aimed at restoring fertility in individuals following germline depletion by genotoxic treatments. This review will discuss regulatory mechanisms of SSCs in homeostatic and regenerative testis and the conservation of these mechanisms between rodent models and man. [ABSTRACT FROM AUTHOR]

Stem cells give rise to all cells and build the tissue structures in our body, and heterogeneity and plasticity are the hallmarks of stem cells. Epigenetic modification, which is associated with niche signals, determines stem cell differentiation and somatic cell reprogramming. Stem cells play a critical role in the development of tumors and are capable of generating 3D organoids. Understanding the properties of stem cells will improve our capacity to maintain tissue homeostasis. Dissecting epigenetic regulation could be helpful for achieving efficient cell reprograming and for developing new drugs for cancer treatment. Stem cell-derived organoids open up new avenues for modeling human diseases and for regenerative medicine. Nevertheless, in addition to the achievements in stem cell research, many challenges still need to be overcome for stem cells to have versatile application in clinics. [ABSTRACT FROM AUTHOR]

Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol's influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor-initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders. [ABSTRACT FROM AUTHOR]

The chemical variability of the intestinal lumen requires the presence of molecular receptors detecting the various substances naturally occurring in the diet and as a result of the activity of the microbiota. Despite their early discovery, intestinal bitter taste receptors (Tas2r) have not yet been assigned an unambiguous physiological function. Recently, using a CRE-recombinant approach we showed that the Tas2r131 gene is expressed in a subset of mucin-producing goblet cells in the colon of mice. Moreover, we also demonstrated that the expression of the Tas2r131 locus is not restricted to this region. In the present study we aimed at characterizing the presence of positive cells also in other gastrointestinal regions. Our results show that Tas2r131 cells appear in the jejunum and the ileum, and are absent from the stomach and the duodenum. We identified the positive cells as a subpopulation of deep-crypt Paneth cells in the ileum, strengthening the notion of a defensive role for Tas2rs in the gut. To get a broader perspective on the expression of bitter taste receptors in the alimentary canal, we quantified the expression of all 35 Tas2r genes along the gastrointestinal tract by qRT-PCR. We discovered that the number and expression level of Tas2r genes profoundly vary along the alimentary canal, with the stomach and the colon expressing the largest subsets. [ABSTRACT FROM AUTHOR]

Renal tubular epithelial cells are exposed to mechanical forces due to fluid flow shear stress within the lumen of the nephron. These cells respond by activation of mechano-sensors located at the plasma membrane or the primary cilium, having crucial roles in maintenance of cellular homeostasis and signaling. In this paper, we applied fluid shear stress to study TGF-β signaling in renal epithelial cells with and without expression of the Pkd1-gene, encoding a mechano-sensor mutated in polycystic kidney disease. TGF-β signaling modulates cell proliferation, differentiation, apoptosis, and fibrotic deposition, cellular programs that are altered in renal cystic epithelia. SMAD2/3-mediated signaling was activated by fluid flow, both in wild-type and Pkd1 cells. This was characterized by phosphorylation and nuclear accumulation of p-SMAD2/3, as well as altered expression of downstream target genes and epithelial-to-mesenchymal transition markers. This response was still present after cilia ablation. An inhibitor of upstream type-I-receptors, ALK4/ALK5/ALK7, as well as TGF-β-neutralizing antibodies effectively blocked SMAD2/3 activity. In contrast, an activin-ligand trap was ineffective, indicating that increased autocrine TGF-β signaling is involved. To study potential involvement of MAPK/ERK signaling, cells were treated with a MEK1/2 inhibitor. Surprisingly, fluid flow-induced expression of most SMAD2/3 targets was further enhanced upon MEK inhibition. We conclude that fluid shear stress induces autocrine TGF-β/ALK5-induced target gene expression in renal epithelial cells, which is partially restrained by MEK1/2-mediated signaling. [ABSTRACT FROM AUTHOR]

CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR. [ABSTRACT FROM AUTHOR]

Next to classical diffusion-based models, filopodia-like cellular protrusions have been proposed to mediate long range signaling events and morphogen gradient formation during communication between distant cells. An increasing wealth of data indicates that in spite of variable characteristics of signaling filopodia in different biological contexts, they represent a paradigm of intercellular crosstalk which is presently being unraveled in a growing literature. Here, we summarize recent advances in investigating the morphology, cellular basis and function of signaling filopodia, with focus on their role during embryonic development in vertebrates. [ABSTRACT FROM AUTHOR]

The thymus provides a specialized microenvironment in which a variety of stromal cells of both hematopoietic and non-hematopoietic origin regulate development and repertoire selection of T cells. Recent studies have been unraveling the inter- and intracellular signals and transcriptional networks for spatiotemporal regulation of development of thymic stromal cells, mainly thymic epithelial cells (TECs), and the molecular mechanisms of how different TEC subsets control T cell development and selection. TECs are classified into two functionally different subsets: cortical TECs (cTECs) and medullary TECs (mTECs). cTECs induce positive selection of diverse and functionally distinct T cells by virtue of unique antigen-processing systems, while mTECs are essential for establishing T cell tolerance via ectopic expression of peripheral tissue-restricted antigens and cooperation with dendritic cells. In addition to reviewing the role of the thymic stroma in conventional T cell development, we will discuss recently discovered novel functions of TECs in the development of unconventional T cells, such as natural killer T cells and γδT cells. [ABSTRACT FROM AUTHOR]

Heparanase is the sole mammalian endoglycosidase that selectively degrades heparan sulfate, the key polysaccharide associated with the cell surface and extracellular matrix of a wide range of tissues. Extensively studied for its capacity to promote cancer progression, heparanase enzyme was recently implicated as an important determinant in several inflammatory disorders as well. Applying immunohistochemical staining, we detected preferential expression of heparanase by epidermal keratinocytes in human psoriatic lesions. To investigate the role of the enzyme in the pathogenesis of psoriasis, we utilized heparanase transgenic mice in a model of 12- O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation. We report that over-expression of the enzyme promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecular/cellular characteristics. Importantly, heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT3, enhanced NF-κB signaling, elevated expression of TNF-α and increased vascularization. Taken together, our results reveal, for the first time, involvement of heparanase in the pathogenesis of psoriasis and highlight a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin. Heparanase inhibitors (currently under clinical testing in malignant diseases) could hence turn highly beneficial in psoriatic patients as well. [ABSTRACT FROM AUTHOR]

Syntrophins are a family of cytoplasmic membrane-associated adaptor proteins, characterized by the presence of a unique domain organization comprised of a C-terminal syntrophin unique (SU) domain and an N-terminal pleckstrin homology (PH) domain that is split by insertion of a PDZ domain. Syntrophins have been recognized as an important component of many signaling events, and they seem to function more like the cell's own personal 'Santa Claus' that serves to 'gift' various signaling complexes with precise proteins that they 'wish for', and at the same time care enough for the spatial, temporal control of these signaling events, maintaining overall smooth functioning and general happiness of the cell. Syntrophins not only associate various ion channels and signaling proteins to the dystrophin-associated protein complex (DAPC), via a direct interaction with dystrophin protein but also serve as a link between the extracellular matrix and the intracellular downstream targets and cell cytoskeleton by interacting with F-actin. They play an important role in regulating the postsynaptic signal transduction, sarcolemmal localization of nNOS, EphA4 signaling at the neuromuscular junction, and G-protein mediated signaling. In our previous work, we reported a differential expression pattern of alpha-1-syntrophin (SNTA1) protein in esophageal and breast carcinomas. Implicated in several other pathologies, like cardiac dys-functioning, muscular dystrophies, diabetes, etc., these proteins provide a lot of scope for further studies. The present review focuses on the role of syntrophins in membrane targeting and regulation of cellular proteins, while highlighting their relevance in possible development and/or progression of pathologies including cancer which we have recently demonstrated. [ABSTRACT FROM AUTHOR]

IgG is a molecule that functionally combines facets of both innate and adaptive immunity and therefore bridges both arms of the immune system. On the one hand, IgG is created by adaptive immune cells, but can be generated by B cells independently of T cell help. On the other hand, once secreted, IgG can rapidly deliver antigens into intracellular processing pathways, which enable efficient priming of T cell responses towards epitopes from the cognate antigen initially bound by the IgG. While this process has long been known to participate in CD4 T cell activation, IgG-mediated delivery of exogenous antigens into a major histocompatibility complex (MHC) class I processing pathway has received less attention. The coordinated engagement of IgG with IgG receptors expressed on the cell-surface (FcγR) and within the endolysosomal system (FcRn) is a highly potent means to deliver antigen into processing pathways that promote cross-presentation of MHC class I and presentation of MHC class II-restricted epitopes within the same dendritic cell. This review focuses on the mechanisms by which IgG-containing immune complexes mediate such cross-presentation and the implications that this understanding has for manipulation of immune-mediated diseases that depend upon or are due to the activities of CD8 T cells. [ABSTRACT FROM AUTHOR]

Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Stem cells are characterized by self-renewal, pluripotency, and quiescence; their long life span, limited capacity to dilute cellular waste and spent organelles due to quiescence, along with their requirement for remodeling in order to differentiate, all suggest that they require autophagy more than other cell types. Here, we review the current literature on the role of autophagy in embryonic and adult stem cells, including hematopoietic, mesenchymal, and neuronal stem cells, highlighting the diverse and contrasting roles autophagy plays in their biology. Furthermore, we review the few studies on stem cells, lysosomal activity, and autophagy. Novel techniques to detect autophagy in primary cells are required to study autophagy in different stem cell types. These will help to elucidate the importance of autophagy in stem cells during transplantation, a promising therapeutic approach for many diseases. [ABSTRACT FROM AUTHOR]

The intestinal epithelium, composed of at least seven differentiated cell types, represents an extraordinary model to understand the details of multi-lineage differentiation, a question that is highly relevant in developmental biology as well as for clinical applications. This review focuses on intestinal epithelial tuft cells that have been acknowledged as a separate entity for more than 60 years but whose function remains a mystery. We discuss what is currently known about the molecular basis of tuft cell fate and differentiation and why elucidating tuft cell function has been so difficult. Finally, we summarize the current hypotheses on their potential involvement in diseases of the gastro-intestinal tract. [ABSTRACT FROM AUTHOR]

The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche. [ABSTRACT FROM AUTHOR]

Autoreactive CD8 regulatory T cells (Tregs) play important roles as modulators of immune responses against self, and numerical and functional defects in CD8 Tregs have been linked to autoimmunity. Several subsets of CD8 Tregs have been described. However, the origin of these T cells and how they participate in the natural progression of autoimmunity remain poorly defined. We discuss several lines of evidence suggesting that the autoimmune process itself promotes the development of autoregulatory CD8 T cells. We posit that chronic autoantigenic exposure fosters the differentiation of non-pathogenic autoreactive CD8 T cells into antigen-experienced, memory-like autoregulatory T cells, to generate a 'negative feedback' regulatory loop capable of countering pathogenic autoreactive effectors. This hypothesis predicts that approaches capable of boosting autoregulatory T cell memory will be able to blunt autoimmunity without compromising systemic immunity. [ABSTRACT FROM AUTHOR]

The scientific interest in the family of the so-called nervous vascular parallels has been growing steadily for the past 15 years, either by addition of new members to the group or, lately, by deepening the analysis of established concepts and mediators. Proteins governing both neurons and vascular cells are known to be involved in events such as cell fate determination and migration/guidance but not in the last and apparently most complex step of nervous system development, the formation and maturation of synapses. Hence, the recent addition to this family of the specific synaptic proteins, Neurexin and Neuroligin, is a double innovation. The two proteins, which were thought to be 'simple' adhesive links between the pre- and post-synaptic sides of chemical synapses, are in fact extremely complex and modulate the most subtle synaptic activities. We will discuss the relevant data and the intriguing challenge of transferring synaptic activities to vascular functions. [ABSTRACT FROM AUTHOR]

Presynaptic differentiation takes place over three interrelated acts involving the biogenesis and trafficking of molecular complexes of active zone material, the “trapping” or stabilization of active zone sites, and the subsequent development of mature synapses. Although the identities of proteins involved with establishing presynaptic specializations have been increasingly delineated, the exact functional mechanisms by which the active zone is assembled remain poorly understood. Here, we discuss a theoretical model for how the trapping stage of presynaptic differentiation might occur in developing neurons. We suggest that subsets of active zone proteins containing polyglutamine domains undergo concentration-dependent prion-like conversions as they accumulate at the plasma membrane. This conversion might serve to aggregate the proteins into a singular structure, which is then able to recruit scaffolding agents necessary for regulated synaptic transmission. A brief informatics analysis in support of this ‘Q’ assembly hypothesis—across commonly used models of synaptogenesis—is presented. [ABSTRACT FROM AUTHOR]

Osteoclasts, the primary cell type mediating bone resorption, are multinucleated, giant cells derived from hematopoietic cells of monocyte-macrophage lineage. Osteoclast activity is, in a large part, regulated by protein-tyrosine phosphorylation. While information about functional roles of several protein-tyrosine kinases (PTK), including c-Src, in osteoclastic resorption has been accumulated, little is known about the roles of protein-tyrosine phosphatases (PTPs) in regulation of osteoclast activity. Recent evidence implicates important regulatory roles for four PTPs (SHP-1, cyt-PTP-ε, PTP-PEST, and PTPoc) in osteoclasts. Cyt-PTP-ε, PTP-PEST, and PTP-oc are positive regulators of osteoclast activity, while SHP-1 is a negative regulator. Of these PTPs in osteoclasts, only PTP-oc is a positive regulator of c-Src PTK through dephosphorylation of the inhibitory phosphotyrosine-527 residue. Although some information about mechanisms of action of these PTPs to regulate osteoclast activity is reviewed in this article, much additional work is required to provide more comprehensive details about their functions in osteoclasts. [ABSTRACT FROM AUTHOR]

Cullin-RING E3 ubiquitin-Ligases (CRLs) are the most prominent class of ubiquitin-ligases. By controlling the stability of a cohort of key regulators, CRLs impinge on many cellular and biological processes such as immunity, development, transcription, cell signalling and cell cycle progression. CRLs are multi-subunit complexes composed of a catalytic site and a substrate recognition module nucleated around a cullin scaffold protein. Most eukaryotic genomes encode at least five distinct cullins, and each of these cullins recruits a specific substrate-recognition module such that CRL complexes are modular. Despite their considerable diversity, CRLs are regulated by similar mechanisms. In particular, recent observations indicate that conformational variability induced by CRL dimerization and by conjugation of the ubiquitin-like protein NEDD8 on the cullin subunit stimulates substrate polyubiquitination. In this review, we discuss the composition of CRL complexes and the various molecular mechanisms controlling their activity. [ABSTRACT FROM AUTHOR]

Syncoilin is a member of the intermediate filament protein family, highly expressed in skeletal and cardiac muscle. Syncoilin binds α-dystrobrevin, a component of the dystrophin associated protein complex (DAPC) located at the muscle cell membrane, and desmin, a muscle-specific intermediate filament protein, thus providing a link between the DAPC and the muscle intermediate filament network. This link may be important for muscle integrity and force transduction during contraction, a theory that is supported by the reduced force-generating capacity of muscles from syncoilin-null mice. Additionally, syncoilin is found at increased levels in the regenerating muscle fibres of patients with muscular dystrophies and mouse models of muscle disease. Therefore, syncoilin may be important for muscle regeneration in response to injury. The aims of this article are to review current knowledge about syncoilin and to discuss its possible functions in skeletal muscle. [ABSTRACT FROM AUTHOR]

As befalls many mediators that act upon the human stage, leukotrienes have become identified with their most powerful roles as villains of the immune system. They are well known for their leading roles in allergic diseases, including asthma. They also have gained recognition for their dramatic role as promoters of inflammation. As new roles for these lipid messengers are sought, it is becoming apparent that the leukotrienes have been typecast as bad guys of the immune system. As examples, their more recent roles have been in atherosclerosis, pulmonary fibrosis and cancer. However, upon further evaluation, we can begin to see their versatility. Thus, leukotrienes stimulate innate immunity against pathogens. In addition, they promote the expression of mediators, receptors and other molecules that are important for immune defense. In these lesser known roles, they lead the fight against bacterial, fungal and viral infection. This review is intended to shed light on the leukotrienes, where they come from and what we really know about them. [ABSTRACT FROM AUTHOR]

Translation of nutrient stimuli through intracellular signaling is important for adaption and regulation of metabolic processes, while deregulation by either genetic or environmental factors predisposes towards the development of metabolic disorders. Besides providing energy, fatty acids act as prominent signaling molecules by altering cell membrane structures, affecting the lipid modification status of proteins, and by modulating ligand-activated nuclear receptor activity. Given their highly hydrophobic nature, fatty acids in the aqueous intracellular compartment are bound to small intracellular lipid binding proteins which function as intracellular carriers of these hydrophobic components. This review describes recent advances in identifying intracellular pathways for cytosolic fatty acid signaling through ligand activated receptors by means of small intracellular lipid binding proteins. The mechanism behind intracellular fatty acid transport and subsequent nuclear receptor activation is an emerging concept, and advances in understanding this process provide new potential therapeutic targets towards the treatment of metabolic disorders. [ABSTRACT FROM AUTHOR]

Lipid homeostasis requires a strict balance between lipid intake and consumption. This balance is controlled by different systems that regulate food intake, energy storage and energy expenditure. This review focuses on the roles of peroxisome proliferator- activated receptors (PPARs) in some of these regulatory processes. PPARs are transcription factors that bind and are activated by fatty acids and fatty acid derivatives. They act as lipid sensors and adapt the metabolism and development of various tissues to lipid availability. Due to their actions on lipid metabolism, PPARs are bona fide therapeutic targets in the treatment of metabolic syndrome not only by affecting gene expression patterns in several tissues but also by inducing remodeling of tissues such as adipose or skeletal muscle. [ABSTRACT FROM AUTHOR]

The germ cell lineage is the sole cell lineage through which genomic information is transmitted into successive generations. To this end, germ cells undergo various specific differentiation steps including meiosis, whose regulation seems to correlate closely with fundamental mechanisms that create differences between germ cells and somatic cells. In mammals, meiosis is triggered by extra-embryonic stimuli such as retinoic acid, which may induce various intracellular molecular cascades promoting meiosis. In addition, the specific epigenetic status arranged in germ cells before and after induction of meiosis, including meiosis-specific transcription control based on histone methylation by a novel histone methyltransferase Meisetz, is also critical for its proper progression. [ABSTRACT FROM AUTHOR]

Smallpox virus eradication was one of the greatest successes of the 20th century. Moreover, the quest to combat its use in biological warfare, has fueled efforts to understand residual immune memory and to develop new animal models by the scientific community. Although the literature is full of animal studies of vaccinia virus infection, continuing efforts have helped to increase our knowledge regarding humoral and cellular memory to non-persistent pathogens and to study factors that might influence further vaccination strategies in humans. In addition, the potent immunostimulatory action of poxvirus vectors has led to development and evaluation of new-generation vaccine candidates, which will be discussed in this review. [ABSTRACT FROM AUTHOR]

Rubinstein-Taybi syndrome (RTS) is a rare human genetic disorder characterized by mental retardation and physical abnormalities. Many RTS patients have a genetic mutation which has been mapped to chromosome 16p13.3, a genomic region encoding cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP). CBP is a transcriptional co-activator that binds to CREB when the latter is phosphorylated and promotes gene transcription. CREB-dependent gene transcription has been shown to underlie long-term memory formation. In this review we will focus on recent findings regarding the biology of CBP and its role in memory formation and cognitive dysfunction in RTS. We will also review the role of CBP in other neurological disorders, including Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Finally, we will discuss novel therapeutic approaches targeted to CBP/CREB function for treating the cognitive dysfunction of RTS and other neurological disorders. [ABSTRACT FROM AUTHOR]

The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally, the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins for assembly of the complex and revealed its importance for brain development and regulation of the ’milieu intérieur. Here, we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the role of dystrophin isoforms and utrophin for assembly of the complex in these tissues. [ABSTRACT FROM AUTHOR]

Tyrosine phosphorylation by unidentified enzymes has been observed in mitochondria, with recent evidence indicating that non-receptorial tyrosine kinases belonging to the Src family, which represent key players in several transduction pathways, are constitutively present in mitochondria. The extent of protein phosphorylation reflects a coordination balance between the activities of specific kinases and phophatases. The present study demonstrates that purified rat brain mitochondria possess endogenous tyrosine phosphatase activity. Mitochondrial phosphatases were found to be capable of dephosphorylating different exogenous substrates, including paranitrophenylphosphate,32P-poly(Glu-Tyr)4:1 and32P-angiotensin. These activities are strongly inhibited by peroxovanadate, a well-known inhibitor of tyrosine phosphatases, but not by inhibitors of alkali or Ser/Thr phosphatases, and mainly take place in the intermembrane space and outer mitochondrial membrane. Using a combination of approaches, we identified the tyrosine phosphatase Shp-2 in mitochondria. Shp-2 plays a crucial role in a number of intracellular signalling cascades and is probably involved in several human diseases. It thus represents the first tyrosine phosphatase shown to be present in mitochondria. [ABSTRACT FROM AUTHOR]

Apart from the lipids present in the nuclear envelope, the nucleus also contains lipids which are located further inside and are resistant to treatment with nonionic detergents. Evidence is being accumulated on the importance of internal nuclear lipid metabolism. Nuclear lipid metabolism gives rise to several lipid second messengers that function within the nucleus. Moreover, it is beginning to emerge that nuclear lipids not only act as precursors of bioactive second messengers but may be directly involved in regulation of nuclear structure and gene expression. Over the last 10years, especially the role of the inositol lipid cycle in nuclear signal transduction has been extensively studied. This cycle is activated following a variety of stimuli and is regulated independently from the inositide cycle located at the plasma membrane. However, the nucleus contain other lipids, such as phosphatidylcholine, sphingomyelin, fatty acids and eicosanoids. There are numerous reports which suggest that these classes of nuclear lipids may play roles in the nucleus as important as those of phosphoinositides. This review aims at highlighting the most important aspects regarding the metabolism and signaling activities of nuclear phosphatidylcholine, sphingomyelin, fatty acids and eicosanoids. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) are nuclear proteins that belong to the superfamily of nuclear hormone receptors. They mediate the effects of small lipophilic compounds such as long-chain fatty acids and their derivatives on transcription of genes commonly called PPAR target genes. Here we review the involvement of PPARα in peroxisomal and mitochondrial fatty acid oxidation, microsomal fatty acid hydroxylation, lipoprotein, bile and amino acid metabolism, glucose homeostasis, biotransformation, inflammation control, hepato-carcinogenesis and other pathways, through a detailed analysis of the different known or putative PPARα target genes. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatases (PTPs) have emerged as a new class of signaling molecules that play important roles in the development and function of the central nervous system. They include both tyrosine-specific and dual-specific phosphatases. Based on their cellular localization they are also classified as receptor-like or intracellular PTP. However, the intracellular mechanisms by which these PTPs regulate cellular signaling pathways are not well understood. Evidence gathered to date provides some insight into the physiological function of these PTPs in the nervous system. In this review, we outline what is currently known about the functional role of PTPs expressed in the brain. [ABSTRACT FROM AUTHOR]

Fatty acid-binding proteins (FABPs) are members of a superfamily of lipid-binding proteins, and occur intracellularly in vertebrates and invertebrates. This review presents recent findings on the diversity of these FABPs and their proposed roles in fatty acid (FA) metabolism and other cellular processes. Special attention is paid to the structural features of the different mammalian FABP types and the physiological role of these proteins in FA transport, cell growth and differentiation, cellular signalling, gene transcription and cytoprotection. Additionally, data on FABP knockout mice and the implication of FABP in medicine are discussed. [ABSTRACT FROM AUTHOR]

Leukotrienes are a family of paracrine hormones derived from the oxidative metabolism of arachidonic acid. These lipid mediators are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems, in particular asthma. Such conditions are typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene B4 is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation. Recently, drugs which block the formation and action of leukotrienes have been introduced as novel antiasthmatic medications. This chapter reviews the biochemistry, molecular biology and cell biology of the key enzymes and cognate receptors in the leukotriene cascade. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. These receptors stimulate transcription after activation by their cognate ligand and binding to the promoter of target genes. In this review, we discuss how fatty acids affect PPAR functions in the cell. We first describe the structural features of the ligand binding domains of PPARs, as defined by crystallographic analyses. We then present the ligand-binding characteristics of each of the three PPARs (α, β/δ, γ) and relate ligand activation to various cellular processes: (i) fatty acid catabolism and modulation of the inflammatory response for PPARα, (ii) embryo implantation, cell proliferation and apoptosis for PPARβ, and (iii) adipocytic differentiation, monocytic differentiation and cell cycle withdrawal for PPARγ. Finally, we present possible cross-talk between the PPAR pathway and different endocrine routes within the cell, including the thyroid hormone and retinoid pathways. [ABSTRACT FROM AUTHOR]

Cell cycle progression is driven by the coordinated regulation of the activities of cyclin-dependent kinases (Cdks). Of the several mechanisms known to regulate Cdk activity in response to external signals, regulation of cyclin gene expression, post-translational modification of Cdks by phosphorylation-dephosphorylation cascades, and the interaction of cyclin/Cdk complexes with protein inhibitors have been thoroughly studied. During recent years, much attention has also been given to mechanisms that regulate protein degradation by the ubiquitin/proteasome pathway, as well as to the regulation of subcellular localization of the proteins that comprise the intrinsic cell cycle clock. The purpose of the present review is to summarize the most important aspects of the various mechanisms implicated in cell cycle regulation. [ABSTRACT FROM AUTHOR]

Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes share regions of sequence similarity, and all predict integral membrane proteins. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern, interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms involved in renal cyst formation. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and have been initially described as molecular targets for compounds which induce peroxisome proliferation. The interest of researchers for PPARs increased dramatically when these receptors were shown to be directly activated by a number of medically relevant compounds. These compounds include: the fibrate class of hypolidemic drugs, the thiazolidinediones, which are insulin sensitizers used as orally active antidiabetic agents, certain non-steroidal anti-inflammatory drugs (NSAIDs), and naturally occurring fatty acid-derived molecules. Rapidly, it was demonstrated that PPARs are key regulators of lipid homeostasis and provide a molecular link between nutrition and gene regulation. Recently, detailed studies of PPAR expression profiles in different tissues pointed to the roles these receptors play in inflammation control and cell proliferation. In this review we will focus on the new insights gained into these two areas and we will also discuss our current knowledge of the regulation of PPAR transcriptional activity by cofactors. [ABSTRACT FROM AUTHOR]

Plant ion channel activities are rapidly modulated in response to several environmental and endogenous stimuli such as light, pathogen attack and phytohormones. Electrophysiological as well as pharmacological studies provide strong evidence that ion channels are essential for the induction of specific cellular responses, implicating their tight linkage to signal transduction cascades. Ion channels propagate signals by modulating the membrane potential or by directly affecting cellular ion composition. In addition, they may also be effectors at the end of signaling cascades, as examplified by ion channels which determine the solute content of stomatal guard cells. Plant channels are themselves subject to regulation by a variety of cellular factors, including calcium, pH and cyclic nucleotides. In addition, they appear to be regulated by (de)-phosphorylation events as well as by direct interactions with cytoskeletal and other cellular proteins. This review summarizes current knowledge on the role of ion chan nels in plant signaling. [ABSTRACT FROM AUTHOR]