Dynorphins, endogenous opioid neuropeptides derived from the prodynorphin gene, are involved in a variety of normative physiologic functions including antinociception and neuroendocrine signaling, and may be protective to neurons and oligodendroglia via their opioid receptor-mediated effects. However, under experimental or pathophysiological conditions in which dynorphin levels are substantially elevated, these peptides are excitotoxic largely through actions at glutamate receptors. Because the excitotoxic actions of dynorphins require supraphysiological concentrations or prolonged tissue exposure, there has likely been little evolutionary pressure to ameliorate the maladaptive, non-opioid receptor mediated consequences of dynorphins. Thus, dynorphins can have protective and/or proapoptotic actions in neurons and glia, and the net effect may depend upon the distribution of receptors in a particular region and the amount of dynorphin released. Increased prodynorphin gene expression is observed in several disease states and disruptions in dynorphin processing can accompany pathophysiological situations. Aberrant processing may contribute to the net negative effects of dysregulated dynorphin production by tilting the balance towards dynorphin derivatives that are toxic to neurons and/or oligodendroglia. Evidence outlined in this review suggests that a variety of CNS pathologies alter dynorphin biogenesis. Such alterations are likely maladaptive and contribute to secondary injury and the pathogenesis of disease.
Opioids; neuropeptides; neuropeptides processing; drug abuse; spinal cord injury; neurotrauma; pain; glutamate; N-methyl-D-aspartate; AMPA; apoptosis; neurotoxicity; excitotoxicity; striatum; κ-opioid receptors
Individuals of many animal species communicate with each other using sounds or “calls” that are made up of basic acoustic patterns and their combinations. We are interested in questions about the processing of communication calls and their representation within the mammalian auditory cortex. Our studies compare in particular two species for which a large body of data has accumulated: the mustached bat and the rhesus monkey. We conclude that the brains of both species share a number of functional and organizational principles, which differ only in the extent to which and how they are implemented. For instance, neurons in both species use “combination-sensitivity” (nonlinear spectral and temporal integration of stimulus components) as a basic mechanism to enable exquisite sensitivity to and selectivity for particular call types. Whereas combination-sensitivity is already found abundantly at the primary auditory cortical and also at subcortical levels in bats, it becomes prevalent only at the level of the lateral belt in the secondary auditory cortex of monkeys. A parallel-hierarchical framework for processing complex sounds up to the level of the auditory cortex in bats and an organization into parallel-hierarchical, cortico-cortical auditory processing streams in monkeys is another common principle. Response specialization of neurons seems to be more pronounced in bats than in monkeys, whereas a functional specialization into “what” and “where” streams in the cerebral cortex is more pronounced in monkeys than in bats. These differences, in part, are due to the increased number and larger size of auditory areas in the parietal and frontal cortex in primates. Accordingly, the computational prowess of neural networks and the functional hierarchy resulting in specializations is established early and accelerated across brain regions in bats. The principles proposed here for the neural “management” of species-specific calls in bats and primates can be tested by studying the details of call processing in additional species. Also, computational modeling in conjunction with coordinated studies in bats and monkeys can help to clarify the fundamental question of perceptual invariance (or “constancy”) in call recognition, which has obvious relevance for understanding speech perception and its disorders in humans.
Language; Speech; Neural coding; Bats; Primates; Review
Cancer chemoprevention by phytochemicals may be one of the most feasible approaches for cancer control. Phytochemicals obtained from vegetables, fruits, spices, teas, herbs and medicinal plants, such as terpenoids and other phenolic compounds, have been proven to suppress experimental carcinogenesis in various organs in pre-clinical models. Recent studies have indicated that mechanisms underlying chemopreventive potential may be a combination of antioxidant, anti-inflammatory, immune-enhancing, and hormone modulation effects, with modification of drug metabolizing enzymes, influence on cell cycle and cell differentiation, induction of apoptosis, suppression of proliferation and angiogenesis playing roles in the initiation and secondary modification stages of neoplastic development. Specific features of prostate cancer, such as high prevalence and long latency period provides ample opportunities for chemopreventive agents to work at various stages of disease progression. Finally, suitable populations with appropriate risk factors, including the presence of pre-malignant lesions and genetic predispositions, need to be well characterized for future chemopreventive interventions. Here we review naturally occurring dietary terpenoids as useful agents for prostate cancer chemoprevention with reference to their classes and sources.
Terpenoids; cancer chemoprevention; biomarkers; prostate cancer
Sepsis is the leading cause of death in medical intensive care units. Though progress has been made in the early treatment of sepsis associated with hemodynamic collapse (septic shock), little is known about the pathogenesis of delayed organ dysfunction during sepsis. A growing body of data indicates that sepsis is associated with acute changes in cell metabolism, and that mitochondria are particularly susceptible. The severity of mitochondrial pathology varies according to host and pathogen factors, and appears to correlate with loss of organ dysfunction. In this regard, low levels of cell apoptosis and mitochondrial turnover are normally observed in all metabolically active tissues; however, these homeostatic mechanisms are frequently overwhelmed during sepsis and contribute to cell and tissue pathology. Thus, a better understanding of the mechanisms regulating mitochondrial damage and repair during severe sepsis may provide new treatment options and better outcomes for this deadly disease (30-60% mortality). Herein, we present compelling evidence linking mitochondrial apoptosis pathways to sepsis-induced cell and organ failure and discuss the implications in terms of future sepsis research.
sepsis; septic shock; severe sepsis; apoptosis; mitochondria; oxidative stress; mitochondria biogenesis; autophagy; Review
In experiments reported here, we tested the ability of CGP-48506 to reverse the depressed cardiac contractility associated with hypercapnic acidosis in isolated rat cardiac myocytes. CGP-48506 is a cardiotonic agent that directly and specifically promotes the actin-cross-bridge reaction. Myocytes superfused at pH 6.8 demonstrated a significantly reduced extent of cell shortening, but an increase in the peak amplitude of the Ca2+ transient. Moreover, cells in acidosis showed small, but significant, decreases in time to peak shortening to 50% relaxation. Superfusion of the cells with 3, 7, and 10 micro-molar CGP-48506 restored the inhibited contractility as a function of concentration with no significant effects on the Ca2+-transient. Moreover, 10 micro-molar CGP-48506 completely reversed the depressed myocyte contraction associated with an increase in time to peak shortening and time to 50% and 75% relaxation. Our results indicate that the depression of contractility associated with acidosis is due to a reduced myofilament response to Ca2+, which can be overcome by agents working downstream from troponin C through a direct effect on the actin-myosin interaction.
Ca2+-sensitizer; Ischemia; Cardiotonic; Contractility; Myocyte Shortening; Ca-Transient
Different gene targeting approaches have been developed to modify endogenous genomic DNA in both human and mouse cells. Briefly, the process involves the targeting of a specific mutation in situ leading to the gene correction and the restoration of a normal gene function. Most of these protocols with therapeutic potential are oligonucleotide based, and rely on endogenous enzymatic pathways. One gene targeting approach, “Small Fragment Homologous Replacement (SFHR)”, has been found to be effective in modifying genomic DNA. This approach uses small DNA fragments (SDF) to target specific genomic loci and induce sequence and subsequent phenotypic alterations. This study shows that SFHR can stably introduce a 3-bp deletion (deltaF508, the most frequent cystic fibrosis (CF) mutation) into the Cftr (CF Transmembrane Conductance Regulator) locus in the mouse embryonic stem (ES) cell genome. After transfection of deltaF508-SDF into murine ES cells, SFHR-mediated modification was evaluated at the molecular levels on DNA and mRNA obtained from transfected ES cells. About 12% of transcript corresponding to deleted allele was detected, while 60% of the electroporated cells completely last any measurable CFTR-dependent chloride efflux The data indicate that the SFHR technique can be used to effectively target and modify genomic sequences in ES cells. Once the SFHR-modified ES cells differentiate into different cell lineages they can be useful for elucidating tissue-specific gene function and for the development of transplantation-based cellular and therapeutic protocols.
Homologous Replacement; Real-Time PCR; SFHR; Embryonic Stem Cells; CFTR
Cytokines play a crucial role in the modulation of inflammatory response in the gastrointestinal tract. Pro-inflammatory cytokines including tumor necrosis factor-α, interferon-γ, interleukin-1β (IL-1β), and interleukin-12 are essential in mediating the inflammatory response, while anti-inflammatory cytokines including interleukin-10 and transforming growth factor-β are important in the attenuation or containment of inflammatory process. It is increasingly recognized that cytokines have an important physiological and pathological effect on intestinal tight junction (TJ) barrier. Consistent with their known pro-inflammatory activities, pro-inflammatory cytokines cause a disturbance in intestinal TJ barrier, allowing increased tissue penetration of luminal antigens. Recent studies indicate that the inhibition of cytokine induced increase in intestinal TJ permeability has an important protective effect against intestinal mucosal damage and development of intestinal inflammation. In this review, the effects of various pro-inflammatory and anti-inflammatory cytokines on intestinal TJ barrier and the progress into the mechanisms that mediate the cytokine modulation of intestinal TJ barrier are reviewed.
Tight Junctions; Cytokines; Intestinal Epithelial Cells; Barrier Function; Inflammation; Review
Proline utilization A proteins (PutAs) are bifunctional enzymes that catalyze the oxidation of proline to glutamate using spatially separated proline dehydrogenase and pyrroline-5-carboxylate dehydrogenase active sites. Here we use the crystal structure of the minimalist PutA from Bradyrhizobium japonicum (BjPutA) along with sequence analysis to identify unique structural features of PutAs. This analysis shows that PutAs have secondary structural elements and domains not found in the related monofunctional enzymes. Some of these extra features are predicted to be important for substrate channeling in BjPutA. Multiple sequence alignment analysis shows that some PutAs have a 17-residue conserved motif in the C-terminal 20–30 residues of the polypeptide chain. The BjPutA structure shows that this motif helps seal the internal substrate-channeling cavity from the bulk medium. Finally, it is shown that some PutAs have a 100–200 residue domain of unknown function in the C-terminus that is not found in minimalist PutAs. Remote homology detection suggests that this domain is homologous to the oligomerization beta-hairpin and Rossmann fold domain of BjPutA.
Proline Utilization A; PutA; Substrate Channeling; Proline Catabolism; Proline Metabolism; Proline Dehydrogenase; Pyrroline-5-Carboxylate Dehydrogenase; Pyrroline-5-Carboxylate; Glutamate Semialdehyde; Domain Repeat; Aldehyde Dehydrogenase; Flavoenzyme; Remote Homology Detection; Review
The presence of cilia in many vertebrate cell types and its function has been ignored for many years. Only in the past few years has its importance been rediscovered. In part, this was triggered by the realization that many gene products mutated in polycystic kidney diseases are localized to cilia and dysfunctional cilia result in kidney disease. Another breakthrough was the observation that the establishment of the left-right body axis is dependent on cilia function. Since then, many other developmental paradigms have been shown to rely on cilia-dependent signaling. In addition to mouse and Chlamydomonas, lower vertebrate model systems such as zebrafish, medaka and Xenopus have provided important new insights into cilia signaling and its role during embryonic development. This review will summarize those studies. We will also illustrate how these lower vertebrates are promising model systems for future studies defining the physiological function of cilia during organogenesis and disease pathophysiology.
Cilia; Left-Right; Kidney; Zebrafish; Medaka; Xenopus; Kidney; PKD; ADPKD; ARPKD; NPHP; BBS; Review
Macrophages are versatile cells involved in health and disease. These cells act as scavengers to rid the body of apoptotic and senescent cells and debris through their phagocytic function. Although this is a primary function of these cells, macrophages play vital roles in inflammation and repair of damaged tissue. Macrophages secrete a large number of cytokines, chemokines and growth factors that recruit and activate a variety of cell types to inflamed tissue compartments. These cells are also critical in cell-mediated immunity and in the resolution of inflammation. Since macrophages, and their precursors, blood monocytes, are important in regulating and resolving inflammation, prolonged cellular survival in tissue compartments could be detrimental. Thus, factors that regulate the fate of monocyte and macrophage survival are important in cellular homeostasis. In this article, we will explore stimuli and the intracellular pathways important in regulating macrophage survival and implication in human disease.
M-CSF; Monocyte; Macrophage; Pulmonary Fibrosis; Atherosclerosis; Breast Cancer; Lung Cancer; PI3K; AKT; Review
Infection by a human papillomavirus (HPV) may result in a variety of clinical conditions ranging from benign warts to invasive cancer depending on the viral type. The HPV E2 protein represses transcription of the E6 and E7 genes in integrated papillomavirus genomes and together with the E1 protein is required for viral replication. E2 proteins bind with high affinity to palindromic DNA sequences consisting of two highly conserved four base pair sequences flanking a variable ‘spacer’ of identical length. The E2 proteins directly contact the conserved DNA but not the spacer DNA. However, variation in naturally occurring spacer sequences results in differential protein binding affinity. This discrimination in binding is dependent on their sensitivity to the unique conformational and/or dynamic properties of the spacer DNA in a process termed ‘indirect readout’. This article explores the structure of the E2 proteins and their interaction with DNA and other proteins, the effects of ions on affinity and specificity, and the phylogenetic and biophysical nature of this core viral protein. We have analyzed the sequence conservation and electrostatic features of three-dimensional models of the DNA binding domains of 146 papillomavirus types and variants with the goal of identifying characteristics that associated with risk of virally caused malignancy. The amino acid sequence, three-dimensional structure, and the electrostatic features of E2 protein DNA binding domain showed high conservation among all papillomavirus types. This indicates that the specific interactions between the E2 protein and its binding sites on DNA have been conserved throughout PV evolution. Analysis of the E2 protein’s transactivation domain showed that unlike the DNA binding domain, the transactivation domain does not have extensive surfaces of highly conserved residues. Rather, the regions of high conservation are localized to small surface patches. The invariance of the E2 DNA binding domain structure, electrostatics and sequence suggests that it may be a suitable target for the development of vaccines effective against a broad spectrum of HPV types.
Papillomavirus; DNA; Protein-DNA interactions; Electrostatics; E2; Review
Metabolic syndrome is a major health issue in the western world. An elevated pro-inflammatory state is often found in patients with metabolic diseases such as type 2 diabetes and obesity. Atherosclerosis is one such clinical manifestation of pro-inflammatory state associated with the vasculature. The exact mechanism by which metabolic stress induces this pro-inflammatory status and promotes atherogenesis remained elusive until the discovery of the inflammasome protein complex. This complex is composed of pro-caspase-1 and pathogen sensors. Activation of inflammasome requires the transcriptional upregulation of inflammasome components and the post-translational assembly. Three models of inflammasome assembly have been proposed: 1) the ion channel model; 2) the reactive oxygen species (ROS) model; and 3) the lysosome model. In either case, inflammasome activation triggers the auto-activation of pro-caspase-1 into its mature form. Caspase-1, which was first discovered as the IL-1β converting enzyme, is known to be a major player in inflammatory and cell death pathways. Many endogenous metabolic ligands have been experimentally shown to activate inflammasome, and thus initiate the subsequent inflammation process. Further understanding of the distinct molecular mechanism by which metabolic ligands activates inflammasome could lead to developing novel therapeutic interventions for atherosclerosis and other clinical problems related to metabolic diseases.
inflammasomes; Caspase-1; ROS; Vascular Inflammation; Interleukin-1 beta; Atherosclerosis; Review
An inhibitor of tissue factor-induced coagulation was rediscovered in the 1980’s and subsequently named tissue factor pathway inhibitor (TFPI). Three isoforms of TFPI are transcribed through alternative mRNA splicing: TFPIα, which contains an acidic aminoterminus followed by three tandem Kunitz-type protease inhibitor domains and a basic carboxyterminus; TFPIβ, in which the Kunitz-3 and carboxyterminus of TFPIα are replaced with a different carboxyterminus containing a glycosyl phosphatidyl inositol (GPI) anchor; and TFPIδ, which is truncated following the Kunitz-2 domain. The microvascular endothelium is thought to be the principal source of TFPI and TFPIα is the predominant isoform expressed in humans. TFPIα, apparently attached to the surface of the endothelium in an indirect GPI-anchor-dependent fashion, represents the greatest in vivo reservoir of TFPI. The Kunitz-2 domain of TFPI is responsible for factor Xa inhibition and the Kunitz-1 domain is responsible for factor Xa-dependent inhibition of the factor VIIa/tissue factor catalytic complex. The anticoagulant activity of TFPI in one-stage coagulation assays is due mainly to its inhibition of factor Xa through a process that is enhanced by protein S and dependent upon the Kunitz-3 and carboxyterminal domains of full-length TFPIα. Carboxyterminal truncated forms of TFPI as well as TFPIα in plasma, however, inhibit factor VIIa/tissue factor in two-stage assay systems. Studies in gene-disrupted mice demonstrate the physiological importance of TFPI.
More than 50 percent of prelingual hearing loss is genetic in origin, and of these up to 93 percent are monogenic autosomal recessive traits. Some forms of genetic deafness can be recognized by their associated syndromic features, but in most cases, hearing loss is the only finding and is referred to as nonsyndromic deafness. To date, more than 700 different mutations have been identified in one of 42 genes in individuals with autosomal recessive nonsyndromic hearing loss (ARNSHL). Reported mutations in GJB2, encoding connexin 26, makes this gene the most common cause of hearing loss in many populations. Other relatively common deafness genes include SLC26A4, MYO15A, OTOF, TMC1, CDH23, and TMPRSS3. In this report we summarize genes and mutations reported in families with ARNSHL. Founder effects were demonstrated for some recurrent mutations but the most significant findings are the extreme locus and allelic heterogeneity and different spectrum of genes and mutations in each population.
Consanguinity; Deafness; Founder effects; Gene; Inner ear; Non syndromic hearing loss; Recurrent mutations; Allelic heterogeneity; Review
Research on the causes and treatments of Alzheimer's disease (AD) has led investigators down numerous avenues. Although many models have been proposed, no single model of AD satisfactorily accounts for all neuropathologic findings as well as the requirement of aging for disease onset. The mechanisms of disease progression are equally unclear. We hypothesize that alternative gene expression during AD plays a critical role in disease progression. Numerous developmentally regulated genes and cell cycle proteins have been shown to be re-expressed or activated during AD. These proteins include transcription factors, members of the cell cycle regulatory machinery, and programmed cell death genes. Such proteins play an important role during brain development and would likely exert powerful effects if re-expressed in the adult brain. We propose that the re-expression or activation of developmentally regulated genes define molecular mechanisms active both during brain development and in AD
Alzheimer's disease; Development; Gene expression; Cell cycle; Transcription
Enamel is a hard nanocomposite bioceramic with significant resilience that protects the mammalian tooth from external physical and chemical damages. The remarkable mechanical properties of enamel are associated with its hierarchical structural organization and its thorough connection with underlying dentin. This dynamic mineralizing system offers scientists a wealth of information that allows the study of basic principals of organic matrix-mediated biomineralization and can potentially be utilized in the fields of material science and engineering for development and design of biomimetic materials. This chapter will provide a brief overview of enamel hierarchical structure and properties as well as the process and stages of amelogenesis. Particular emphasis is given to current knowledge of extracellular matrix protein and proteinases, and the structural chemistry of the matrix components and their putative functions. The chapter will conclude by discussing the potential of enamel for regrowth.
Amelogenesis; Enamel; Amelogenin; Biomineralization; Tooth; Review
Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. This study is to investigate transcriptional mechanism underlying homocysteine (Hcy)-induced and monocytes (MC)-derived inflammatory response. We identified 11 Hcy-induced genes, 17 anti-inflammatory cytokine interleukin 10-induced, 8 pro-inflammatory cytokine interferon γ (IFNγ)-induced and 8 pro-inflammatory cytokine tumor necrosis factor α (TNFα)-induced genes through literature search. Binding frequency of 36 transcription factors (TFs) implicated in inflammation and MC differentiation were analyzed within core promoter regions of identified genes, and classified into 3 classes based on the significant binding frequency to the promoter of Hcy-induced genes. Class 1 TFs exert high significant binding frequency in Hcy-induced genes. Class 2 and 3 TFs have low and no significant binding frequency, respectively. Class 1 TF binding occurrence in Hcy-induced genes is similar to that in IFNγ-induced genes, but not that in TNFα-induced. We conclude that Hcy is a pro-inflammatory amino acid and induces inflammatory transcriptional signal pathways mediated by class 1 TF. We term class 1 TF, which includes heat shock factor, MC enhancer factor-2, nuclear factor of activated T-cells, nuclear factor kappa light chain enhancer of activated B cells and Krueppel-like factor 4, as putative Hcy-responsive TFs.
Pulmonary surfactant, a lipoprotein complex, maintains alveolar integrity and plays an important role in lung host defense, and control of inflammation. Altered inflammatory processes and surfactant dysfunction are well described events that occur in patients with acute or chronic lung disease that can develop secondary to a variety of insults. Genetic variants of surfactant proteins, including single nucleotide polymorphisms, haplotypes, and other genetic variations have been associated with acute and chronic lung disease throughout life in several populations and study groups. The hydrophilic surfactant proteins SP-A and SP-D, also known as collectins, in addition to their surfactant-related functions, are important innate immunity molecules as these, among others, exhibit the ability to bind and enhance clearance of a wide range of pathogens and allergens. This review focuses on published association studies of human surfactant proteins A and D genetic polymorphisms with respiratory, and non-respiratory diseases in adults, children, and newborns. The potential role of genetic variations in pulmonary disease or pathogenesis is discussed following an evaluation, and comparison of the available literature.
SFTPA1; SFTPA2; SP-D; Polymorphism; Single Nucleotide; collectins; lung disease; review
Despite advances in surgery, radiation therapy, and chemotherapy, patients with cancer have a dismal prognosis. Sustained aberrant tumor angiogenesis and metastasis is a major obstacle for effective cancer treatment. Just a few years ago, few would argue that one of the key success stories of the modern cancer medicine are the anti-angiogenic drugs targeting the VEGF signaling pathway approved by FDA. This success inspires many researchers to quest for new anti-angiogenic targets and drugs with the hope that one day, anti-angiogenic therapy might really become the panacea for cancer patients. However, the limited clinical benefits with anti-angiogenic drugs conflicts with the widely accepted notion that angiogenesis is a key event in tumor progression. Emerging data indicate that unique characteristics of tumor vasculature in the tumor microenvironment may hold a key for success of anti-angiogenic therapy. In particular, the molecular and cellular alterations that sustain aberrant tumor angiogenesis in the face of angiogenic inhibitors represents novel targets for rationally designing anti-angiogenic strategies and improving current anti-angiogenic therapies.
tumor angiogenesis; anti-angiogenic therapy; vasculature; endothelial cells
The small DNA genome of hepadnaviruses is replicated by reverse transcription via an RNA intermediate. This RNA “pregenome” contains important signals that control critical steps of viral replication, including RNA packaging, initiation of reverse transcription, and elongation of minus strand DNA, through specific interactions with the viral reverse transcriptase, the capsid protein, and host factors. In particular, the interaction between the viral reverse transcriptase and RNA pregenome requires a host chaperone complex composed of the heat shock protein 90 and its cochaperones.
Hepadnavirus; Hepatitis B virus; Hsp90; Protein Priming; Reverse Transcription; RNA packaging; Review
B cells exhibit a range of functional responses following TLR engagement including immunoglobulin and cytokine production, proliferation, antigen presentation and migration. However, B cell intrinsic TLR responses appear to be precisely programmed based upon the developmental stage of the cell. B cell subpopulations classified as innate immune cells including marginal zone and B-1 B cells exhibit robust responses to TLR stimulation. In contrast, activation of other B cell subsets is constrained via a variety of developmentally regulated events. In this review we provide an overview of TLR responses in murine and human B cells and specifically highlight patterns of TLR expression and developmentally regulated functional responses.
B cell subpopulations; Marginal zone B cells; Transitional B cells; Follicular mature B cells; B-1 B cells; BAFF; TRL; MyD88; IRAK-4 deficient patients; MyD88 deficient patients; LPS; CpG; R848; Review
The mRNA-binding protein AUF1 regulates the expression of many key players in cancer including proto-oncogenes, regulators of apoptosis and the cell cycle, and pro-inflammatory cytokines, principally by directing the decay kinetics of their encoded mRNAs. Most studies support an mRNA-destabilizing role for AUF1, although other findings suggest additional functions for this factor. In this review, we explore how changes in AUF1 isoform distribution, subcellular localization, and post-translational protein modifications can influence the metabolism of targeted mRNAs. However, several lines of evidence also support a role for AUF1 in the initiation and/or development of cancer. Many AUF1-targeted transcripts encode products that control pro- and anti-oncogenic processes. Also, overexpression of AUF1 enhances tumorigenesis in murine models, and AUF1 levels are enhanced in some tumors. Finally, signaling cascades that modulate AUF1 function are deregulated in some cancerous tissues. Together, these features suggest that AUF1 may play a prominent role in regulating the expression of many genes that can contribute to tumorigenic phenotypes, and that this post-transcriptional regulatory control point may be subverted by diverse mechanisms in neoplasia.
AUF1; alternative splicing; RNA turnover; RNA-binding protein; phosphorylation; cancer; review
The major event that triggers osteogenesis is the transition of mesenchymal stem cells into bone forming, differentiating osteoblast cells. Osteoblast differentiation is the primary component of bone formation, exemplified by the synthesis, deposition and mineralization of extracellular matrix. Although not well understood, osteoblast differentiation from mesenchymal stem cells is a well-orchestrated process. Recent advances in molecular and genetic studies using gene targeting in mouse enable a better understanding of the multiple factors and signaling networks that control the differentiation process at a molecular level. Osteoblast commitment and differentiation are controlled by complex activities involving signal transduction and transcriptional regulation of gene expression. We review Wnt signaling pathway and Runx2 regulation network, which are critical for osteoblast differentiation. Many other factors and signaling pathways have been implicated in regulation of osteoblast differentiation in a network manner, such as the factors Osterix, ATF4, and SATB2 and the TGF-beta, Hedgehog, FGF, ephrin, and sympathetic signaling pathways. This review summarizes the recent advances in the studies of signaling transduction pathways and transcriptional regulation of osteoblast cell lineage commitment and differentiation. The knowledge of osteoblast commitment and differentiation should be applied towards the development of new diagnostic and therapeutic alternatives for human bone diseases.
Osteoblast; Runx2; Osterix; ATF4; SATB2; Wnt signaling; TGF-Beta signaling; hedgehog signaling; fgf signaling; ephrin signaling; sympathetic signaling; Review
A key regulator of proliferation, differentiation and cell fate, the c-Myb transcription factor regulates the expression of hundreds of genes and is in turn regulated by numerous pathways and protein interactions. However, the most unique feature of c-Myb is that it can be converted into an oncogenic transforming protein through a few mutations that completely change its activity and specificity. The c-Myb protein is a myriad of interactions and activities rolled up in a protein that controls proliferation and differentiation in many different cell types. Here we discuss the background and recent progress that have led to a better understanding of this complex protein, and outline the questions that have yet to be answered.
Myb; Oncogene; Stem Cells; Hematopoiesis; Transformation; Transcription; Post-Translational Modifications; Protein-Protein Interactions; SND1; cell cycle; SANT domain; Review
Our research attempted to address two important questions - how microRNAs modulate atherogenic inflammatory genes from a panoramic viewpoint and whether their augmented expression results from reduced microRNAs suppression. To resolve these knowledge gaps, we employed a novel database mining technique in conjunction with statistical analysis criteria established from experimentally verified microRNAs. We found that the expression of 33 inflammatory genes up-regulated in atherosclerotic lesions contain structural features in the 3′UTR of their mRNAs for potential microRNAs regulation. Additionally, the binding features governing the interactions between the microRNAs and the inflammatory gene mRNA were statistically identical to the features of experimentally verified microRNAs. Furthermore, 21 (64%) of the 33 inflammatory genes were targeted by highly expressed microRNAs and 10 of these (48%) were targeted by a single microRNA, suggesting microRNA regulation specificity. Supplementing our findings, seven out of the 20 unique microRNAs were previously confirmed to be down-regulated when treated with pro-atherogenic factors. These results indicate a critical role of anti-inflammatory microRNAs in suppressing pro-atherogenic inflammatory gene expression.
microRNAs; mRNA stability; inflammatory genes; atherosclerosis; vascular inflammation