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The apparently large genetic contribution to the aetiology of mental illness presents a formidable puzzle. Unlike common physical disorders, mental illness usually has an onset early in the reproductive age and is associated with substantial reproductive disadvantage. Therefore, genetic variants associated with vulnerability to mental illness should be under strong negative selection pressure and be eliminated from the genetic pool through natural selection. Still, mental disorders are common and twin studies indicate a strong genetic contribution to their aetiology. Several theories have been advanced to explain the paradox of high heritability and reproductive disadvantage associated with the same common phenotype, but none provides a satisfactory explanation for all types of mental illness. At the same time, identification of the molecular substrate underlying the large genetic contribution to the aetiology of mental illness is proving more difficult than expected. The quest for genetic variants associated with vulnerability to mental illness is predicated upon the common disease/common variant (CDCV) hypothesis. On the basis of a summary of evidence, it is concluded that the CDCV hypothesis is untenable for most types of mental illness. An alternative evolution-informed framework is proposed, which suggests that gene-environment interactions and rare genetic variants constitute most of the genetic contribution to mental illness. Common mental illness with mild reproductive disadvantage is likely to have a large contribution from interactions between common genetic variants and environmental exposures. Severe mental illness that confers strong reproductive disadvantage is likely to have a large and pleiotropic contribution from rare variants of recent origin. This framework points to a need for a paradigm change in genetic research to enable major progress in elucidating the aetiology of mental illness.
Mol Psychiatry 2009 Dec
PMID:The role of genetic variation in the causation of mental illness: an evolution-informed framework. 1970 9

Cellular membranes can assume a number of highly dynamic shapes. Many cellular processes also require transient membrane deformations. Membrane shape is determined by the complex interactions of proteins and lipids. A number of families of proteins that directly bend membranes have been identified. Most associate transiently with membranes and deform them. These proteins work by one or more of three types of mechanisms. First, some bend membranes by inserting amphipathic domains into one of the leaflets of the bilayer; increasing the area of only one leaflet causes the membrane to bend. Second, some proteins form a rigid scaffold that deforms the underlying membrane or stabilizes an already bent membrane. Third, some proteins may deform membranes by clustering lipids or by affecting lipid ordering in membranes. Still other proteins may use novel but poorly understood mechanisms. In this review, we summarize what is known about how different families of proteins bend membranes.
Crit Rev Biochem Mol Biol
PMID:Membrane-bending proteins. 1978 Jun 39

The microtubule (MT) network is essential in a broad spectrum of cellular functions. Many studies have linked CENP-F to MT-based activities as disruption of this protein leads to major changes in MT structure and function. Still, the basis of CENP-F regulation of the MT network remains elusive. Here, our studies reveal a novel and critical localization and role for CENP-F at the centrosome, the major MT organizing center (MTOC) of the cell. Using a yeast two-hybrid screen, we identify Hook2, a linker protein that is essential for regulation of the MT network at the centrosome, as a binding partner of CENP-F. With recently developed immunochemical reagents, we confirm this interaction and reveal the novel localization of CENP-F at the centrosome. Importantly, in this first report of CENP-F(-/-) cells, we demonstrate that ablation of CENP-F protein function eliminates MT repolymerization after standard nocodazole treatment. This inhibition of MT regrowth is centrosome specific because MT repolymerization is readily observed from the Golgi in CENP-F(-/-) cells. The centrosome-specific function of CENP-F in the regulation of MT growth is confirmed by expression of truncated CENP-F containing only the Hook2-binding domain. Furthermore, analysis of partially reconstituted MTOC asters in cells that escape complete repolymerization block shows that disruption of CENP-F function impacts MT nucleation and anchoring rather than promoting catastrophe. Our study reveals a major new localization and function of CENP-F at the centrosome that is likely to impact a broad array of MT-based actions in the cell.
Mol Biol Cell 2009 Nov
PMID:Murine CENP-F regulates centrosomal microtubule nucleation and interacts with Hook2 at the centrosome. 1979 14

Over the last few decades, advances in cultivation-independent methods have significantly contributed to our understanding of microbial diversity and community composition in the environment. At the same time, cultivation-dependent methods have thrived, and the growing number of organisms obtained thereby have allowed for detailed studies of their physiology and genetics. Still, most microorganisms are recalcitrant to cultivation. This review not only conveys current knowledge about different isolation and cultivation strategies but also discusses what implications can be drawn from pure culture work for studies in microbial ecology. Specifically, in the light of single-cell individuality and genome heterogeneity, it becomes important to evaluate population-wide measurements carefully. An overview of various approaches in microbial ecology is given, and the cell as a central unit for understanding processes on a community level is discussed.
Microbiol Mol Biol Rev 2009 Dec
PMID:Central role of the cell in microbial ecology. 1994 38

The ideal vector for cell and tissue modification does not depend on integration but rather behaves as an independent functional unit that replicates as an episome. Based on a scaffold/matrix attachment region (S/MAR), we have introduced, in 2006, an approximately 4-kb replicating nonviral minicircle able to exploit the cellular replication machinery in a way reminiscent of ARS vectors. Consisting of only one active transcription unit and the S/MAR, it resists silencing as it is free of prokaryotic vector parts and drug selection markers. The rate of final establishment in the nuclear architecture is moderate but comparable to Epstein-Barr virus-based episomes (<5%). Here, we demonstrate that this parameter can be improved if the host cell chromatin is opened by histone hyperacetylation prior to transfection. It remains unaffected, however, by cell cycle position. Still, this class of episomes revealed intrinsic instability and integration after 5 months of continuous culture. In vivo evolution enabled the effective reduction of S/MAR size from 2 kb to 733 bp (resulting in a minicircle of approximately 3 kb) with largely improved stability and cloning capacity. Investigation of individual clones served to prove persistent and homogenous expression, which is ascribed to stable association with nuclear attachment sites. Optimum expression levels were shown to depend on the authentic usage of a polyadenylation site 3' from the S/MAR as anticipated by the stress-induced duplex destabilization algorithm, which finds increasing use to predict the functional parameters of these systems.
J Mol Biol 2010 Feb 05
PMID:Minicircle performance depending on S/MAR-nuclear matrix interactions. 2000 66

To paraphrase Robert Burns's poem To a Mouse, the best laid schemes of DNA-protein complex purification often go awry. Chromatin with its heterogeneous and dynamic protein composition remains difficult to analyze. Still critical progress has been made in recent years in characterizing the interface between DNA and proteins due, in part, to significant advances in proteomic technologies. Proteomics has progressed to a point where affinity purification of soluble complexes and protein identification by mass spectrometry are routine. The new challenge for chromatin proteomics lies in studying proteins and protein complexes in their native environment, which is on chromatin. These novel types of data represent an additional layer of information that can be used to better characterize and understand cellular processes. This review will focus on the past contributions as well as on emerging mass spectrometry-based methodologies attempting to better define the complex relationship between proteins, protein complexes and DNA.
Mol Biosyst 2010 Jan
PMID:Of proteins and DNA--proteomic role in the field of chromatin research. 2002 64

Magnetic resonance (MR) is one of the most widely used imaging modalities in contemporary medicine to obtain images of pathological areas. Still, there is a big effort to facilitate the accumulation of contrast in the required zone and further increase a local spatial concentration of a contrast agent for better imaging. Certain particulate carriers able to carry multiple contrast moieties can be used for an efficient delivery of contrast agents to areas of interest and enhancing a signal from these areas. Among those carriers, liposomes draw special attention because of their easily controlled properties and good pharmacological characteristics. To enhance the signal intensity from a given reporter metal in liposomes, one may attempt to increase the net quantity of carrier-associated reporter metal by using polylysine (PLL)-based polychelating amphiphilic polymers (PAP). In addition to heavy load of reporter metal onto the pharmaceutical nanocarrier (liposome), the accumulation of the contrast nanoparticles in organs and tissues of interest (such as tumors) can be significantly enhanced by targeting such particles both "passively," via the so-called enhanced permeability and retention (EPR) effect, or "actively," using various target-specific ligands, such as monoclonal antibodies. Combining three different properties--heavy load with Gd via the liposome membrane-incorporated PAP and tumor specificity mediated by the liposome-attached mAb 2C5--in a single nanoparticle of long-circulating (PEGylated) liposomes could provide a new contrast agent for highly specific and efficient tumor MRI.
Methods Mol Biol 2010
PMID:Gadolinium-loaded polychelating polymer-containing tumor-targeted liposomes. 2007 91

Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive beta-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote beta-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production.
Mol Pharmacol 2010 May
PMID:Functional characterization of vasopressin type 2 receptor substitutions (R137H/C/L) leading to nephrogenic diabetes insipidus and nephrogenic syndrome of inappropriate antidiuresis: implications for treatments. 2015 41

Genes for individual domains such as CH, lim, ankyrin, PH and RhoGAP, IQ motif, Ig_FLMN, spectrin, and EF hand probably existed in early evolution before there were plants, fungi or animals so that when we examine multidomain proteins in Arabidopsis, Saccharomyces, Dictyostelium or Homo Sapiens we encounter various combinations of such domains. While all of these four species express Fimbrin and EB1, the lists of CH containing multidomain proteins, however, differ in number and in type for each of them. There was no further great increase in the number of new single domain proteins. Still many new multidomain genes evolved--but far more so in metazoans--than in plants or fungi. In both plants and fungi only singlet CH domains but no doublets (other than those forming the Fimbrin quadruplet) were incorporated. That is in these two branches one finds no alpha actinin, dystrophin or filamin even though the individual building blocks (i.e. domains such as spectrin or IG-FLMN) were available in Arabidopsis. Possibly transposons create new chimeric multidomain genes by mixing and matching genes or gene fragments.
Mol Biol Rep 2011 Jan
PMID:Single and multiple CH (calponin homology) domain containing multidomain proteins in Arabidopsis and Saccharomyces: an inventory. 2034 40

The development of noninvasive screening tests would represent a major advance in the fight against cancer, as pre-clinical or early diagnosis could be considered the best weapons to reduce cancer mortality. The use of autoantibodies against cancer autoantigens is a promising alternative to fulfill this goal. Recent progress in protein microarray formats and other proteomic strategies has brought extraordinary opportunities to advance the discovery of new cancer autoantigens. These new approaches have allowed identification of autoantibodies with a higher prevalence, simplifying the development of predictor panels with wider coverage. Still, some issues have to be resolved before clinical application of these results. First, technical limitations in the quality and reproducibility of the microarrays and the statistical tools for data analysis have to be resolved. Second, thorough validation of the candidate biomarkers has to be carried out to include not just one particular cancer type but different cancers and other benign, inflammatory pathologies, which may give rise to cross-reactions and loss of the specificity and sensitivity of the predictive assay. The extraordinary sensitivity of the immune system to detect minor alterations in self-proteins might be used to highlight changes in the cancer protein sequence and structure that can be used for personalized therapy, including immunotherapeutic vaccines. The increasing detection of kinase proteins as autoantibody targets points to new molecules with potential therapeutic impact.
Mol Diagn Ther 2010 Jun 01
PMID:Identification of cancer autoantigens in serum: toward diagnostic/prognostic testing? 2056 Jun 76


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