| 17344846 |
Patterns of somatic mutation in human cancer genomes. |
10.1038/nature05610 |
Nature |
Patterns of somatic mutation in human cancer genomes.
Abstract
- Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
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| 17347799 |
Regulation of insulin receptor function |
10.1007/s00018-007-6359-9. |
Cell Mol Life Sci |
Regulation of insulin receptor function
Abstract
- Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human disease, is reviewed in this article.
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| 17349580 |
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity |
10.1016/j.ccr.2006.12.017. |
Cancer Cell |
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity
Abstract
- Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788, and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme.
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| 17369307 |
Inhibition of vascular endothelial growth factor cotranslational translocation by the cyclopeptolide CAM741 |
10.1124/mol.107.034249. |
Mol Pharmacol |
Inhibition of vascular endothelial growth factor cotranslational translocation by the cyclopeptolide CAM741
Abstract
- The cyclopeptolide CAM741 inhibits cotranslational translocation of vascular cell adhesion molecule 1 (VCAM1), which is dependent on its signal peptide. We now describe the identification of the signal peptide of vascular endothelial growth factor (VEGF) as the second target of CAM741. The mechanism by which the compound inhibits translocation of VEGF is very similar or identical to that of VCAM1, although the signal peptides share no obvious sequence similarities. By mutagenesis of the VEGF signal peptide, two important regions, located in the N-terminal and hydrophobic segments, were identified as critical for compound sensitivity. CAM741 alters positioning of the VEGF signal peptide at the translocon, and increasing hydrophobicity in the h-region reduces compound sensitivity and causes a different, possibly more efficient, interaction with the translocon. Although CAM741 is effective against translocation of both VEGF and VCAM1, the derivative NFI028 is able to inhibit only VCAM1, suggesting that chemical derivatization can alter not only potency, but also the specificity of the compounds.
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| 17369852 |
SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1 |
10.1038/sj.onc.1210387. |
Oncogene |
SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1
Abstract
- The nuclear protein p68 (also known as Ddx5) is a prototypic member of the 'DEAD box' family of RNA helicases, which has been shown to be abnormally expressed and modified in colorectal tumors and to function as an important transcriptional regulator. Here, we show that p68 is modified in vivo on a single site (K53) by the small ubiquitin-like modifier-2 (SUMO-2). We demonstrate that the SUMO E3 ligase PIAS1 interacts with p68 and enhances its SUMO modification in vivo. To determine the functional consequences of SUMO modification, we compared the transcriptional activity of p68 and a K53R mutant that could not be SUMO-modified. Our data show that SUMO modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53. These findings may be explained by the ability of wild type, but not K53R p68, to alter the modification state of chromatin by recruitment of histone deacetylase 1 (HDAC1).
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| 17373667 |
Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases. |
10.1002/ijc.22673 |
Int. J. |
Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases.
Abstract
- The PLU-1/JARID1B nuclear protein, which is expressed in a high proportion of breast cancers, but shows restricted expression elsewhere, belongs to the ARID family of proteins, known to play important roles in development, differentiation, transcriptional regulation and chromatin remodeling. PLU-1/JARID1B is a strong transcriptional repressor, and here we show that the protein localizes in MAD bodies when cotransfected with class IIa histone deacetylases (HDACs) or N-CoR. Direct binding to class I and class IIa HDACs is demonstrated, while the interaction with N-CoR appears to be indirect. The domains involved in the HDAC4-PLU-1/JARID1B interaction were investigated in detail, and the data show that 2 PHD domains in PLU-1/JARID1B, which are involved in transcriptional repression, are also crucial for binding to a domain in the 5' region of HDAC4, overlapping the MEF-2 binding region. Physiological relevance of this interaction in the mammary gland is suggested from the observation that HDAC4 and PLU-1/JARID1B are coexpressed in the pregnant and involuting mouse mammary gland and are both silenced at lactation. Significantly, the expression of both proteins is seen in breast cancers.
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| 17373804 |
Thalassospiramides A and B, immunosuppressive peptides from the marine bacterium Thalassospira sp |
10.1021/ol070294u. |
Org Lett |
Thalassospiramides A and B, immunosuppressive peptides from the marine bacterium Thalassospira sp
Abstract
- [structure: see text] Two new cyclic peptides, thalassospiramides A and B (1 and 2), were isolated from a new member of the marine alpha-proteobacterium Thalassospira. The thalassospiramides, the structures of which were assigned by combined spectral and chemical methods, bear unusual gamma-amino acids and show immunosuppressive activity in an interleukin-5 production inhibition assay (IC50 = 5 muM for thalassospiramide B).
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| 17378610 |
Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes |
10.1021/np070007v. |
J Nat Prod |
Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes
Abstract
- In recent years, the cyclotides have emerged as the largest family of naturally cyclized proteins. Cyclotides display potent cytotoxic activity that varies with the structure of the proteins, and combined with their unique structure, they represent novel cytotoxic agents. However, their mechanism of action is yet unknown. In this work we show that disruption of cell membranes plays a crucial role in the cytotoxic effect of the cyclotide cycloviolacin O2 (1), which has been isolated from Viola odorata. Cell viability and morphology studies on the human lymphoma cell line U-937 GTB showed that cells exposed to 1 displayed disintegrated cell membranes within 5 min. Functional studies on calcein-loaded HeLa cells and on liposomes showed rapid concentration-dependent release of their respective internal contents. The present results show that cyclotides have specific membrane-disrupting activity.
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| 17391387 |
The effect of aminocandin (HMR 3270) on the in-vitro adherence of Candida albicans to polystyrene surfaces coated with extracellular matrix proteins or fibronectin |
10.1111/j.1469-0691.2006.01644.x. |
Clin Microbiol Infect |
The effect of aminocandin (HMR 3270) on the in-vitro adherence of Candida albicans to polystyrene surfaces coated with extracellular matrix proteins or fibronectin
Abstract
- Aminocandin is a new representative of the echinocandins that could potentially affect the cellular morphology and metabolic status of Candida albicans cells within biofilms. This study investigated the influence of a sub-inhibitory concentration (MIC/2) of aminocandin on in-vitro growth of C. albicans and subsequent fungal adherence to plastic surfaces coated with fibronectin or extracellular matrix (ECM) proteins. Eleven strains of C. albicans were studied, of which six were susceptible and five were resistant to fluconazole. All 11 strains were susceptible to aminocandin in vitro, regardless of the culture medium used for the microdilution method. Aminocandin induced a significant (p <0.005) decrease in adherence when polystyrene was coated with ECM gel (ten strains) or fibronectin (seven strains). Growth in medium containing aminocandin (MIC/2) decreased the adherence of five (ECM gel) or three (fibronectin) of the six strains susceptible to fluconazole, and inhibition was observed for all five (ECM gel) or four (fibronectin) of the five fluconazole-resistant strains. Overall, the study demonstrated the anti-adherent properties of aminocandin with fluconazole-susceptible strains, and suggested that this activity was at least equivalent with fluconazole-resistant strains. Thus, the ability of aminocandin to inhibit the first step in the development of C. albicans biofilms appeared to be independent of the in-vitro resistance of C. albicans to fluconazole.
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| 17400270 |
From the identification of gene organization of alpha conotoxins to the cloning of novel toxins |
10.1016/j.toxicon.2007.02.011. |
Toxicon |
From the identification of gene organization of alpha conotoxins to the cloning of novel toxins
Abstract
- In the venoms of cone snails, alpha conotoxins are competitive antagonists of nicotinic acetylcholine receptors. Eleven novel cDNA and eight partial gene sequences (including two pseudogenes) of alpha conotoxins were identified from five species of cone snail. As expected, every cDNA encodes a precursor of prepropeptide. In all the partial genes of alpha conotoxins identified, there is a long intron inserted at a fixed position in the pro-region, dividing the encoding region into two exons. The mutation rate in exon I (encoding the signal peptide and a part of pro-region) is much lower than that in exon II (encoding the other part of pro-region, the mature peptide and 3' untranslational region). Interestingly, the sequences at the 5' and 3' end of introns are highly conserved. In addition, in the identified introns exist long dinucleotide (e.g. "GT", "CA") or trinucleotide ("CAT") repeats. In the special case of Pu 1.1, there are five almost identical repeats of a 150 bp sequence in the long intron. Taking advantage of the conserved 3' end sequence of intron, 16 alpha conotoxins, as well as a pseudogene and three kappa A conotoxins, were identified from their genomic DNAs. Based on the comparison of these cDNA and gene sequences, a hypothesis of the alpha conotoxin evolution was proposed.
|
| 17432033 |
Part VII. Macrolides, azalides, ketolides, lincosamides, and streptogramins |
None |
J Okla State Med Assoc |
Part VII. Macrolides, azalides, ketolides, lincosamides, and streptogramins
Abstract
- In this article we describe antimicrobials that are grouped by their similar mechanism of action, namely inhibition of protein synthesis at the bacterial 50S ribosomal subunit. Macrolides, azalides, and ketolides are primarily used to treat community acquired respiratory tract infections. A lincosamide antibiotic, clindamycin, is primarily used to treat anaerobic infections. A combination of streptogramins, quinupristin/dalfopristin, is used to treat infections due to multiple drug resistant Gram positive cocci.
|
| 17437523 |
Solution structure of an M-1 conotoxin with a novel disulfide linkage |
10.1111/j.1742-4658.2007.05795.x. |
FEBS J |
Solution structure of an M-1 conotoxin with a novel disulfide linkage
Abstract
- The M-superfamily of conotoxins has a typical Cys framework (-CC-C-C-CC-), and is one of the eight major superfamilies found in the venom of the cone snail. Depending on the number of residues located in the last Cys loop (between Cys4 and Cys5), the M-superfamily family can be divided into four branches, namely M-1, -2, -3 and -4. Recently, two M-1 branch conotoxins (mr3e and tx3a) have been reported to possess a new disulfide bond arrangement between Cys1 and Cys5, Cys2 and Cys4, and Cys3 and Cys6, which is different from those seen in the M-2 and M-4 branches. Here we report the 3D structure of mr3e determined by 2D (1)H NMR in aqueous solution. Twenty converged structures of this peptide were obtained on the basis of 190 distance constraints obtained from NOE connectivities, as well as six varphi dihedral angle, three hydrogen bond, and three disulfide bond constraints. The rmsd values about the averaged coordinates of the backbone atoms were 0.43 +/- 0.19 A. Although mr3e has the same Cys arrangement as M-2 and M-4 conotoxins, it adopts a distinctive backbone conformation with the overall molecule resembling a 'flying bird'. Thus, different disulfide linkages may be employed by conotoxins with the same Cys framework to result in a more diversified backbone scaffold.
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| 17441146 |
Toward the total synthesis of onchidin, a cytotoxic cyclic depsipeptide from a mollusc |
10.1002/asia.200600232. |
Chem Asian J |
Toward the total synthesis of onchidin, a cytotoxic cyclic depsipeptide from a mollusc
Abstract
- The total synthesis of onchidin (1), a cytotoxic, C2-symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel beta-amino acid, (2S,3S)-3-amino-2-methyl-7-octynoic acid (AMO), was efficiently prepared in high yield with high diastereo- and enantioselectivity based on a catalytic asymmetric three-component Mannich-type reaction with a chiral zirconium catalyst. The formation of sterically unfavorable N-methyl amide and hindered ester bonds were successfully demonstrated, and final macrocyclization was achieved at a secondary-amide site. Completion of the synthesis of 1 suggested that a revision of the structure of the natural product is required. Two diastereomers were also synthesized as candidates for the actual structure of onchidin. Furthermore, efficient solid-phase methods were employed for the combinatorial synthesis of other derivatives to clarify the real structure of onchidin. The solid-phase assembly of a pentadepsipeptide containing all the building blocks was established followed by dimeric cyclization in solution.
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| 17451843 |
Peptide defenses of the Cascades frog Rana cascadae: implications for the evolutionary history of frogs of the Amerana species group |
10.1016/j.peptides.2007.03.010. |
Peptides |
Peptide defenses of the Cascades frog Rana cascadae: implications for the evolutionary history of frogs of the Amerana species group
Abstract
- The Cascades frog Rana cascadae belongs to the Amerana (or Rana boylii) group that includes six additional species from western North America (R. aurora, R. boylii, R. draytonii, R. luteiventris, R. muscosa, and R. pretiosa). R. cascadae is particularly susceptible to pathogenic microorganisms in the environment and populations have declined precipitously in parts of its range so that the protection afforded by dermal antimicrobial peptides may be crucial to survival of the species. Peptidomic analysis of norepinephrine-stimulated skin secretions led to the identification of six peptides with differential cytolytic activities that were present in high abundance. Structural characterization showed that they belonged to the ranatuerin-2 (one peptide), brevinin-1 (one peptide), and temporin (four peptides) families. Ranatuerin-2CSa (GILSSFKGVAKGVAKDLAGKLLETLKCKITGC) and brevinin-1CSa (FLPILAGLAAKIVPKLFCLATKKC) showed broad spectrum antibacterial activity (MIC</=32microM against Escherichia coli and Staphylococcus aureus) but only brevinin-1CSa was strongly hemolytic against human erythrocytes (LC(50)=5microM). The taxonomy of ranid frogs is currently in a considerable state of flux. The ranatuerin-2 gene is expressed in all members of the Amerana group studied to-date and cladistic analysis based upon a comparison of the amino acid sequences of this peptide indicates that R. cascadae, R. muscosa and R. aurora form a clade that is distinct from one containing R. draytonii, R. boylii, and R. luteiventris. This conclusion is consistent with previous analyses based upon comparisons of the nucleotide sequences of mitochondrial genes.
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| 17461417 |
Acutely increased cyclophilin a expression after brain injury: a role in blood-brain barrier function and tissue preservation |
10.1002/jnr.21324. |
J Neurosci Res |
Acutely increased cyclophilin a expression after brain injury: a role in blood-brain barrier function and tissue preservation
Abstract
- Blood-brain barrier (BBB) compromise is a significant pathologic event that manifests early following traumatic brain injury (TBI). Because many signaling cascades are initiated immediately after the traumatic event, we were interested in examining acute differential protein expression that may be involved in BBB function. At acute time points postinjury, altered protein expression may result from altered translation efficiency or turnover rate rather than from a genomic response. The application of tandem 2-D gel electrophoresis and mass spectrometry analysis is a powerful approach for directly screening differential protein expression following TBI. Using comparative 2-D gel analysis, we selected candidate protein spots with apparent altered expression and identified them by mass spectrometry. Cyclophilin A was selected for further analysis because it has been implicated in endothelial cell activation and inflammation, and studies have suggested cyclosporine A, an inhibitor of all cyclophilin isoforms, might be beneficial after TBI. We examined if altered expression of cyclophilin A in the brain vasculature might play a role in BBB function. We found significantly increased cyclophilin A levels in isolated brain microvessels 30 min following injury. Postinjury administration of cyclosporine A significantly attenuated BBB permeability measured 24 hr postinjury, suggesting cyclophilin activity after TBI may be detrimental. However, direct injection of purified recombinant cyclophilin A attenuated both BBB permeability and tissue damage in a stab wound model of injury. These findings suggest that increased expression of cyclophilin A may play a protective role after TBI, whereas other cyclophilin isoforms may be detrimental.
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