Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

E6-AP is a 100-kDa cellular protein that interacts with the E6 protein of the cancer-associated human papillomavirus types 16 and 18. The E6/E6-AP complex binds to and targets the p53 tumor-suppressor protein for ubiquitin-mediated proteolysis. E6-AP is an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. The amino acid sequence of E6-AP shows similarity to a number of protein sequences over an approximately 350-aa region corresponding to the carboxyl termini of both E6-AP and the E6-AP-related proteins. Of particular note is a conserved cysteine residue within the last 32-34 aa, which in E6-AP is likely to be the site of ubiquitin thioester formation. Two of the E6-AP-related proteins, a rat 100-kDa protein and a yeast 95-kDa protein (RSP5), both of previously unknown function, are shown here to form thioesters with ubiquitin. Mutation of the conserved cysteine residue of these proteins destroys their ability to accept ubiquitin. These data strongly suggest that the rat 100-kDa protein and RSP5, as well as the other E6-AP-related proteins, belong to a class of functionally related E3 ubiquitin-protein ligases, defined by a domain homologous to the E6-AP carboxyl terminus (hect domain).
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PMID:A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. 776 80

Gene expression of the cancer-associated human papillomavirus (HPV) type 18 is modulated by cis-regulatory elements located within the viral upstream regulatory region (URR). All cellular factors identified so far involved in viral gene control bind to the 3' portion of the HPV-18 URR. In contrast, very little is known about regulatory elements within the 5' portion of the URR. We therefore analysed this region of unknown function to delineate potential cis-regulatory elements contained therein. By utilizing transient expression assays, an 84 bp fragment could be identified in the 5' portion of the URR that exhibits orientation-independent cis-stimulatory activity in HeLa cervical carcinoma cells and primary human fibroblasts. Gel retardation assays and competition experiments indicated specific binding of cellular proteins to the 84 bp fragment. By functional dissection, a regulatory element with intrinsic cis-stimulatory activity could be mapped within the 84 bp fragment. Binding studies indicate that this cis-stimulatory element contains a sequence-aberrant Sp1 recognition site. Transient luciferase assays performed with mutated templates demonstrate that this Sp1 binding site behaves as a functional Sp1 element in vivo and is a main determinant of the cis-stimulatory activity exerted by the 84 bp fragment. These data show that the 5' portion of the HPV-18 URR contains cis-activating elements and indicate an important functional role for the cellular transcription factor Sp1 in their regulation.
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PMID:A novel cis-stimulatory element maps to the 5' portion of the human papillomavirus type 18 upstream regulatory region and is functionally dependent on a sequence-aberrant Sp1 binding site. 838 69

AAA+ ATPases are ubiquitous proteins that employ the energy obtained from ATP hydrolysis to remodel proteins, DNA, or RNA. The MoxR family of AAA+ proteins is widespread throughout bacteria and archaea but is largely uncharacterized. Limited work with specific members has suggested a potential role as molecular chaperones involved in the assembly of protein complexes. As part of an effort aimed at determining the function of novel AAA+ chaperones in Escherichia coli, we report the characterization of a representative member of the MoxR family, YieN, which we have renamed RavA (regulatory ATPase variant A). We show that the ravA gene exists on an operon with another gene encoding a protein, YieM, of unknown function containing a Von Willebrand Factor Type A domain. RavA expression is under the control of the sigmaS transcription factor, and its levels increase toward late log/early stationary phase, consistent with its possible role as a general stress-response protein. RavA functions as an ATPase and forms hexameric oligomers. Importantly, we demonstrate that RavA interacts strongly with inducible lysine decarboxylase (LdcI or CadA) forming a large cage-like structure consisting of two LdcI decamers linked by a maximum of five RavA oligomers. Surprisingly, the activity of LdcI does not appear to be affected by binding to RavA in a number of in vitro and in vivo assays, however, complex formation results in the stimulation of RavA ATPase activity. Data obtained suggest that the RavA-LdcI interaction may be important for the regulation of RavA activity against its targets.
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PMID:Formation of a distinctive complex between the inducible bacterial lysine decarboxylase and a novel AAA+ ATPase. 1630 13

We present the application of a mathematical method reported earlier by which the van der Waals-Platteeuw statistical mechanical model with the Lennard-Jones and Devonshire approximation can be posed as an integral equation with the unknown function being the intermolecular potential between the guest molecules and the host molecules. This method allows us to solve for the potential directly for hydrates for which the Langmuir constants are computed, either from experimental data or from ab initio data. Given the assumptions made in the van der Waals-Platteeuw model with the spherical-cell approximation, there are an infinite number of solutions; however, the only solution without cusps is a unique central-well solution in which the potential is at a finite minimum at the center to the cage. From this central-well solution, we have found the potential well depths and volumes of negative energy for 16 single-component hydrate systems: ethane (C2H6), cyclopropane (C3H6), methane (CH4), argon (Ar), and chlorodifluoromethane (R-22) in structure I; and ethane (C2H6), cyclopropane (C3H6), propane (C3H8), isobutane (C4H10), methane (CH4), argon (Ar), trichlorofluoromethane (R-11), dichlorodifluoromethane (R-12), bromotrifluoromethane (R-13B1), chloroform (CHCl3), and 1,1,1,2-tetrafluoroethane (R-134a) in structure II. This method and the calculated cell potentials were validated by predicting existing mixed hydrate phase equilibrium data without any fitting parameters and calculating mixture phase diagrams for methane, ethane, isobutane, and cyclopropane mixtures. Several structural transitions that have been determined experimentally as well as some structural transitions that have not been examined experimentally were also predicted. In the methane-cyclopropane hydrate system, a structural transition from structure I to structure II and back to structure I is predicted to occur outside of the known structure II range for the cyclopropane hydrate. Quintuple (L(w)-sI-sII-L(hc)-V) points have been predicted for the ethane-propane-water (277.3 K, 12.28 bar, and x(eth,waterfree) = 0.676) and ethane-isobutane-water (274.7 K, 7.18 bar, and x(eth,waterfree) = 0.81) systems.
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PMID:Application of the cell potential method to predict phase equilibria of multicomponent gas hydrate systems. 1685 53

Identification of functionally relevant differences between induced pluripotent stem cells (iPSC) and reference embryonic stem cells (ESC) remains a central question for therapeutic applications. Differences in gene expression between iPSC and ESC have been examined by microarray and more recently with RNA-SEQ technologies. We here report an in depth analyses of nuclear and cytoplasmic transcriptomes, using the CAGE (cap analysis of gene expression) technology, for 5 iPSC clones derived from mouse lymphocytes B and 3 ESC lines. This approach reveals nuclear transcriptomes significantly more complex in ESC than in iPSC. Hundreds of yet not annotated putative non-coding RNAs and enhancer-associated transcripts specifically transcribed in ESC have been detected and supported with epigenetic and chromatin-chromatin interactions data. We identified super-enhancers transcriptionally active specifically in ESC and associated with genes implicated in the maintenance of pluripotency. Similarly, we detected non-coding transcripts of yet unknown function being regulated by ESC specific super-enhancers. Taken together, these results demonstrate that current protocols of iPSC reprogramming do not trigger activation of numerous cis-regulatory regions. It thus reinforces the need for already suggested deeper monitoring of the non-coding transcriptome when characterizing iPSC clones. Such differences in regulatory transcript expression may indeed impact their potential for clinical applications.
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PMID:Nuclear transcriptome profiling of induced pluripotent stem cells and embryonic stem cells identify non-coding loci resistant to reprogramming. 2566 6

Copy number variation (CNV) plays a role in pathogenesis of many human diseases, especially cancer. Several whole genome CNV association studies have been performed for the purpose of identifying cancer associated CNVs. Here we undertook a novel approach to whole genome CNV analysis, with the goal being identification of associations between CNV of different genes (CNV-CNV) across 60 human cancer cell lines. We hypothesize that these associations point to the roles of the associated genes in cancer, and can be indicators of their position in gene networks of cancer-driving processes. Recent studies show that gene associations are often non-linear and non-monotone. In order to obtain a more complete picture of all CNV associations, we performed omnibus univariate analysis by utilizing dCov, MIC, and HHG association tests, which are capable of detecting any type of association, including non-monotone relationships. For comparison we used Spearman and Pearson association tests, which detect only linear or monotone relationships. Application of dCov, MIC and HHG tests resulted in identification of twice as many associations compared to those found by Spearman and Pearson alone. Interestingly, most of the new associations were detected by the HHG test. Next, we utilized dCov's and HHG's ability to perform multivariate analysis. We tested for association between genes of unknown function and known cancer-related pathways. Our results indicate that multivariate analysis is much more effective than univariate analysis for the purpose of ascribing biological roles to genes of unknown function. We conclude that a combination of multivariate and univariate omnibus association tests can reveal significant information about gene networks of disease-driving processes. These methods can be applied to any large gene or pathway dataset, allowing more comprehensive analysis of biological processes.
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PMID:Function of cancer associated genes revealed by modern univariate and multivariate association tests. 2596 68

A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.
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PMID:Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes. 2654 30