p53 Signaling Pathway: July 2012

Tuesday, July 31, 2012

Hydrogen sulfide as a regulator of calcium channels.

Hydrogen sulfide as a regulator of calcium channels.

Cell Calcium. 2012 Jul 25;

Authors: Munaron L, Avanzato D, Moccia F, Mancardi D

Abstract
An increasing body of evidence suggests the involvement of hydrogen sulfide (H(2)S) in different physiological and pathological processes. Similarly to the other gasotransmitters nitric oxide (NO) and carbon monoxide (CO), this bioactive compound is rapidly diffusible through the biological membranes and acts in a paracrine fashion. Despite the large amount of biological actions observed in vitro and in vivo upon stimulation with H(2)S donors, as well as by interfering with its synthesis, the molecular targets and mechanisms through which it exerts its intracellular effects are only partially known. A number of proteins are covalently modified by H(2)S through sulfhydration of specific cysteine residues. However, only in few cases their identity has been discovered and the functional role of this post-translational modification needs to be investigated in more detail. Great attention has been devoted to potassium channels, particularly K(ATP), as they are considered key mediators of H(2)S-induced effects, and their sulfhydration has been clearly demonstrated. Recently, different authors reported the ability of H(2)S to interfere with calcium homeostasis in neurons, cardiomyocytes and endothelial cells. Since calcium signaling is involved in all cell processes, these observations attracted increasing attention from basic biology and medicine. Although some effects of H(2)S on calcium signals can be ascribed to K(ATP) modulation, there is growing consensus about the existence of other targets for the gasotransmitter. Some of them are Ca(2+)-permeable channels. In this review we discuss the state of the art in this specific field, providing an updated report of H(2)S interaction with Ca(2+) channels and its functional outcomes.

PMID: 22840338 [PubMed - as supplied by publisher]

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On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

Chemphyschem. 2012 Jul 24;

Authors: Hintersteiner M, Buehler C, Auer M

Abstract
Conceptually, on-bead screening is one of the most efficient high-throughput screening (HTS) methods. One of its inherent advantages is that the solid support has a dual function: it serves as a synthesis platform and as a screening compartment. Compound purification, cleavage and storage and extensive liquid handling are not necessary in bead-based HTS. Since the establishment of one-bead one-compound library synthesis, the properties of polymer beads in chemical reactions have been thoroughly investigated. However, the characterization of the kinetics and thermodynamics of protein-ligand interactions on the beads used for screening has received much less attention. Consequently, the majority of reported on-bead screens are based on empirically derived procedures, independent of measured equilibrium constants and rate constants of protein binding to ligands on beads. More often than not, on-bead screens reveal apparent high affinity binders through strong protein complexation on the matrix of the solid support. After decoding, resynthesis, and solution testing the primary hits turn out to be unexpectedly weak binders, or may even fall out of the detection limit of the solution assay. Only a quantitative comparison of on-bead binding and solution binding events will allow systematically investigating affinity differences as function of protein and small molecule properties. This will open up routes for optimized bead materials, blocking conditions and other improved assay procedures. By making use of the unique features of our previously introduced confocal nanoscanning (CONA) method, we investigated the kinetic and thermodynamic properties of protein-ligand interactions on TentaGel beads, a popular solid support for on-bead screening. The data obtained from these experiments allowed us to determine dissociation constants for the interaction of bead-immobilized ligands with soluble proteins. Our results therefore provide, for the first time, a comparison of on-bead versus solution binding thermodynamics. Our data indicate that affinity ranges found in on-bead screening are indeed narrower compared to equivalent interactions in homogeneous solution. A thorough physico-chemical understanding of the molecular recognition between proteins and surface bound ligands will further strengthen the role of on-bead screening as an ultimately cost-effective method in hit and lead finding.

PMID: 22829563 [PubMed - as supplied by publisher]

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Monday, July 30, 2012

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

Chemphyschem. 2012 Jul 24;

Authors: Hintersteiner M, Buehler C, Auer M

PMID: 22829563 [PubMed - as supplied by publisher]

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Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study.

Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study.

BMC Pediatr. 2012;12:33

Authors: Puumala SE, Nelson HH, Ross JA, Nguyen RH, Damario MA, Spector LG

Abstract
BACKGROUND: While a possible link between assisted reproductive technology (ART) and rare imprinting disorders has been found, it is not clear if this is indicative of subtler disruptions of epigenetic mechanisms. Results from previous studies have been mixed, but some methylation differences have been observed.
METHODS: Children conceived through ART and children conceived spontaneously were recruited for this cross-sectional study. Information about reproductive history, demographic factors, birth characteristics, and infertility treatment was obtained from maternal interview and medical records. Peripheral blood lymphocytes and buccal cell samples were collected from participating children. Methylation analysis was performed on five loci using pyrosequencing. Statistical analysis of methylation differences was performed using linear regression with generalized estimating equations. Results are reported as differences with 95% confidence intervals (CI).
RESULTS: A total of 67 ART children and 31 spontaneously conceived (SC) children participated. No significant difference in methylation in lymphocyte samples was observed between groups for any loci. Possible differences were found in buccal cell samples for IGF2 DMR0 (Difference: 2.07; 95% confidence interval (CI): -0.28, 4.42; p = 0.08) and IGF2R (Difference: -2.79; 95% CI: -5.74, 0.16; p = 0.06). Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility.
CONCLUSIONS: Observed differences in methylation between the ART and SC groups were small for all loci in the two sample types examined and no statistical differences were observed. It is still unclear whether or not small differences observed in several studies represent a real difference between groups and if this difference is biologically meaningful. Larger studies with long term follow-up are needed to fully answer these questions.

PMID: 22433799 [PubMed - indexed for MEDLINE]

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On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

Chemphyschem. 2012 Jul 24;

Authors: Hintersteiner M, Buehler C, Auer M

PMID: 22829563 [PubMed - as supplied by publisher]

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1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate.

1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate.

J Med Chem. 2012 Mar 22;55(6):2882-93

Authors: Ramnauth J, Renton P, Dove P, Annedi SC, Speed J, Silverman S, Mladenova G, Maddaford SP, Zinghini S, Rakhit S, Andrews J, Lee DK, Zhang D, Porreca F

Abstract
Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC(50) = 4.7 ?M). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC(50) > 30 ?M). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate.

PMID: 22335555 [PubMed - indexed for MEDLINE]

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The unusual mycobacterial chaperonins: evidence for in vivo oligomerization and specialization of function.

The unusual mycobacterial chaperonins: evidence for in vivo oligomerization and specialization of function.

Mol Microbiol. 2012 Jul 26;

Authors: Fan M, Rao T, Zacco E, Ahmed MT, Shukla A, Ojha A, Freeke J, Robinson CV, Benesch JL, Lund PA

Abstract
The pathogen Mycobacterium tuberculosis expresses two chaperonins, one (Cpn60.1) dispensable and one (Cpn60.2) essential. These proteins have been reported not to form oligomers despite the fact that oligomerization of chaperonins is regarded as essential for their function. We show here that the Cpn60.2 homologue from Mycobacterium smegmatis also fails to oligomerize under standard conditions. However, we also show that the Cpn60.2 proteins from both organisms can replace the essential groEL gene of Escherichia coli, and that they can function with E.?coli GroES cochaperonin, as well as with their cognate cochaperonin proteins, strongly implying that they form oligomers in vivo. We show that the Cpn60.1 proteins, but not the Cpn60.2 proteins, can complement for loss of the M.?smegmatis cpn60.1 gene. We investigated the oligomerization of the Cpn60.2 proteins using analytical ultracentrifugation and mass spectroscopy. Both form monomers under standard conditions, but they form higher order oligomers in the presence of kosmotropes and ADP or ATP. Under these conditions, their ATPase activity is significantly enhanced. We conclude that the essential mycobacterial chaperonins, while unstable compared to many other bacterial chaperonins, do act as oligomers in vivo, and that there has been specialization of function of the mycobacterial chaperonins following gene duplication.

PMID: 22834700 [PubMed - as supplied by publisher]

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Sunday, July 29, 2012

1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate.

J Med Chem. 2012 Mar 22;55(6):2882-93

Authors: Ramnauth J, Renton P, Dove P, Annedi SC, Speed J, Silverman S, Mladenova G, Maddaford SP, Zinghini S, Rakhit S, Andrews J, Lee DK, Zhang D, Porreca F

PMID: 22335555 [PubMed - indexed for MEDLINE]

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These pubmed results were generated on 2012/07/28

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Phage-display library biopanning as a novel approach to identifying nematode vaccine antigens.

Phage-display library biopanning as a novel approach to identifying nematode vaccine antigens.

Parasite Immunol. 2012 May;34(5):285-95

Authors: Ellis SE, Newlands GF, Nisbet AJ, Matthews JB

Abstract
Infections with parasitic nematodes are of significant welfare and economic importance worldwide, and because of the emergence of anthelmintic resistance, this has lead to alternative methods of parasite control being required. Vaccination offers a feasible alternative control, and the majority of research has focused on the production of recombinant versions of native antigens previously identified as protective in vaccinated animals. Attempts at the production of protective recombinant subunit vaccines have been hindered, however, as these antigens have invariably failed to replicate the same level of protective immune response as seen with the native versions. It has been proposed that these failures are owing to the fact that the recombinant proteins do not contain the appropriate post-translational modifications to retain the protective capacity of the native molecules. In this review, we discuss a novel approach to vaccine antigen identification through the application of random peptide phage-display libraries and their use to identify peptide sequences that potentially mimic the structure(s) of antigenic epitopes. This area of research is still relatively novel with respect to parasites, and the current state of the art will be discussed here.

PMID: 21770973 [PubMed - indexed for MEDLINE]

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In situ click chemistry: from small molecule discovery to synthetic antibodies.

In situ click chemistry: from small molecule discovery to synthetic antibodies.

Integr Biol (Camb). 2012 Jul 26;

Authors: Millward SW, Agnew HD, Lai B, Lee SS, Lim J, Nag A, Pitram S, Rohde R, Heath JR

Abstract
Advances in the fields of proteomics, molecular imaging, and therapeutics are closely linked to the availability of affinity reagents that selectively recognize their biological targets. Here we present a review of Iterative Peptide In Situ Click Chemistry (IPISC), a novel screening technology for designing peptide multiligands with high affinity and specificity. This technology builds upon in situ click chemistry, a kinetic target-guided synthesis approach where the protein target catalyzes the conjugation of two small molecules, typically through the azide-alkyne Huisgen cycloaddition. Integrating this methodology with solid phase peptide libraries enables the assembly of linear and branched peptide multiligands we refer to as Protein Catalyzed Capture Agents (PCC Agents). The resulting structures can be thought of as analogous to the antigen recognition site of antibodies and serve as antibody replacements in biochemical and cell-based applications. In this review, we discuss the recent progress in ligand design through IPISC and related approaches, focusing on the improvements in affinity and specificity as multiligands are assembled by target-catalyzed peptide conjugation. We compare the IPISC process to small molecule in situ click chemistry with particular emphasis on the advantages and technical challenges of constructing antibody-like PCC Agents.

PMID: 22836343 [PubMed - as supplied by publisher]

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Nitric oxide inhibits the ATPase activity of the chaperone-like AAA+ATPase CDC48, a target for S-nitrosylation in cryptogein signaling in tobacco cells.

Nitric oxide inhibits the ATPase activity of the chaperone-like AAA+ATPase CDC48, a target for S-nitrosylation in cryptogein signaling in tobacco cells.

Biochem J. 2012 Jul 27;

Authors: Astier J, Besson-Bard A, Lamotte O, Bertoldo J, Bourque S, Terenzi H, Wendehenne D

Abstract
Nitric oxide (NO) has important physiological functions in plants including the adaptative response to pathogen attack. We previously demonstrated that cryptogein, an elicitor of defense reaction produced by the oomycete Phytophthora cryptogea, triggers NO synthesis in tobacco. To decipher the role of NO in tobacco cells elicited by cryptogein, here we performed a proteomic approach in order to identify proteins undergoing S-nitrosylation. We provided evidence that cryptogein induced the S-nitrosylation of several proteins and identified 11 candidates including CDC48, a member of the AAA+ATPases. In vitro, NtCDC48 was shown to be poly-S-nitrosylated by NO donors and we could identify Cys-110, Cys-526 and Cys-664 as a targets for S-nitrosylation. Cys-526 is located in the Walker A motif of the D2 domain involved in ATP binding and was previously reported to be regulated by oxidative modification in drosophila. We investigated the consequence of NtCDC48 S-nitrosylation and found that NO abolished NtCDC48 ATPase activity and induced slight conformation changes in the vicinity of Cys-526. Similarly, substitution of Cys-526 by an Ala residue impacted NtCDC48 activity. More generally, our study identified CDC48 as a new candidate for S-nitrosylation in plants facing biotic stress and further supports the importance of Cys-526 in the regulation of CDC48 by oxidative/nitrosative agents.

PMID: 22835150 [PubMed - as supplied by publisher]

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Saturday, July 28, 2012

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

Chemphyschem. 2012 Jul 24;

Authors: Hintersteiner M, Buehler C, Auer M

PMID: 22829563 [PubMed - as supplied by publisher]

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The unusual mycobacterial chaperonins: evidence for in vivo oligomerization and specialization of function.

The unusual mycobacterial chaperonins: evidence for in vivo oligomerization and specialization of function.

Mol Microbiol. 2012 Jul 26;

Authors: Fan M, Rao T, Zacco E, Ahmed MT, Shukla A, Ojha A, Freeke J, Robinson CV, Benesch JL, Lund PA

PMID: 22834700 [PubMed - as supplied by publisher]

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Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study.

Similar DNA methylation levels in specific imprinting control regions in children conceived with and without assisted reproductive technology: a cross-sectional study.

BMC Pediatr. 2012;12:33

Authors: Puumala SE, Nelson HH, Ross JA, Nguyen RH, Damario MA, Spector LG

PMID: 22433799 [PubMed - indexed for MEDLINE]

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Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels.

Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels.

Proc Natl Acad Sci U S A. 2012 May 15;109(20):7899-904

Authors: Bankston JR, Camp SS, DiMaio F, Lewis AS, Chetkovich DM, Zagotta WN

Abstract
Ion channels operate in intact tissues as part of large macromolecular complexes that can include cytoskeletal proteins, scaffolding proteins, signaling molecules, and a litany of other molecules. The proteins that make up these complexes can influence the trafficking, localization, and biophysical properties of the channel. TRIP8b (tetratricopetide repeat-containing Rab8b-interacting protein) is a recently discovered accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that contributes to the substantial dendritic localization of HCN channels in many types of neurons. TRIP8b interacts with the carboxyl-terminal region of HCN channels and regulates their cell-surface expression level and cyclic nucleotide dependence. Here we examine the molecular determinants of TRIP8b binding to HCN2 channels. Using a single-molecule fluorescence bleaching method, we found that TRIP8b and HCN2 form an obligate 4:4 complex in intact channels. Fluorescence-detection size-exclusion chromatography and fluorescence anisotropy allowed us to confirm that two different domains in the carboxyl-terminal portion of TRIP8b--the tetratricopepide repeat region and the TRIP8b conserved region--interact with two different regions of the HCN carboxyl-terminal region: the carboxyl-terminal three amino acids (SNL) and the cyclic nucleotide-binding domain, respectively. And finally, using X-ray crystallography, we determined the atomic structure of the tetratricopepide region of TRIP8b in complex with a peptide of the carboxy-terminus of HCN2. Together, these experiments begin to uncover the mechanism for TRIP8b binding and regulation of HCN channels.

PMID: 22550182 [PubMed - indexed for MEDLINE]

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A slow gradient approach for the purification of synthetic polypeptides by reversed phase high performance liquid chromatography.

A slow gradient approach for the purification of synthetic polypeptides by reversed phase high performance liquid chromatography.

J Pept Sci. 2012 Jul 25;

Authors: Harris PW, Lee DJ, Brimble MA

Abstract
Unquestionably, the purification of polypeptides by chromatographic methods is a considerable bottleneck in their preparation. Peptides synthesised by solid phase synthesis typically contain chromatographically similar impurities that complicate purification by reversed phase high performance liquid chromatography (HPLC) techniques. We report on the application of a slow gradient HPLC protocol that allows, in a single chromatographic step, the purification of hundreds of milligrammes of material. This technique was applied to an extensive collection of synthetic polypeptides some incorporating non-proteinogenic functionality. In all cases examined, the peptides were not only obtained in high purity peptides but were also recovered in multi-milligramme amounts. Copyright � 2012 European Peptide Society and John Wiley & Sons, Ltd.

PMID: 22833387 [PubMed - as supplied by publisher]

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Friday, July 27, 2012

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Genetically distinct subsets within ANCA-Associated Vasculitis.

Genetically distinct subsets within ANCA-Associated Vasculitis.

N Engl J Med. 2012 Jul 19;367(3):214-23

Authors: Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, Baslund B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P, Feighery C, Gross WL, Guillevin L, Gunnarsson I, Harper L, Hru?kov� Z, Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD, Salama AD, Sanders JS, Savage CO, Segelmark M, Stegeman CA, Tesa? V, Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG, Smith KG

Abstract
BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.
METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.
RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding ?(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2�10(-89), P=5.6�10(-12,) and P=2.6�10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1�10(-8)).
CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

PMID: 22808956 [PubMed - indexed for MEDLINE]

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Identification of Two DNA Helicases UvrD and DinG as Suppressors for Lethality Caused by Mutant cspA mRNAs.

Identification of Two DNA Helicases UvrD and DinG as Suppressors for Lethality Caused by Mutant cspA mRNAs.

J Mol Microbiol Biotechnol. 2012 Jul 24;22(3):135-146

Authors: Hwang J, Lee K, Phadtare S, Inouye M

Abstract
CspA is a major cold shock-inducible protein (70 aa), and its major role in the cold shock response was shown to be as an RNA chaperone destabilizing secondary structure of mRNAs at low temperature. Previously, we showed that the overexpression of mutant cspA containing premature non-sense codons at various positions led to stalled ribosomes on mutant cspA transcripts, ultimately leading to cell death. This lethality is primarily due to the highly translatable cspA 5'-UTR that recruits most of the ribosomes from other mRNAs, which are then stalled at the abnormal stop codon. This was called the 'LACE' effect. We show here that non-sense mutation even at the 67th position as well as substitutions of aromatic amino acid residues present on the RNA-binding surface of CspA protein to alanine caused the LACE effect by trapping a substantial amount of ribosomes on cspA mRNAs. In an attempt to identify a suppressor(s), which may help the cells to recover from the inhibitory LACE effect, genetic screening of an Escherichia coli genomic library was performed. We isolated suppressors that contained the genomic fragments encoding uvrD and dinG, respectively, whose gene products are ATP-dependent DNA helicases. The nucleic acid-binding and ATPase activities of these two helicases were found to be essential for their suppression activity. This genomic screening offers an approach to shed light on the mechanistic of 5'-UTR of cspA mRNA and novel roles of E. coli helicases that function in DNA repair.

PMID: 22832783 [PubMed - as supplied by publisher]

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Thursday, July 26, 2012

Bile acids acutely stimulate insulin secretion of mouse ?-cells via farnesoid X receptor activation and K(ATP) channel inhibition.

Bile acids acutely stimulate insulin secretion of mouse ?-cells via farnesoid X receptor activation and K(ATP) channel inhibition.

Diabetes. 2012 Jun;61(6):1479-89

Authors: D�fer M, H�rth K, Wagner R, Schittenhelm B, Prowald S, Wagner TF, Oberwinkler J, Lukowski R, Gonzalez FJ, Krippeit-Drews P, Drews G

Abstract
Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic ?-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and ?-cell ATP-dependent K(+) (K(ATP)) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of ?-cells and enhanced cytosolic Ca(2+) concentration ([Ca(2+)](c)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca(2+)](c) and insulin secretion. FXR activation by TCDC is suggested to inhibit K(ATP) current. The decline in K(ATP) channel activity by TCDC was only observed in ?-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on ?-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K(ATP) channel inhibition.

PMID: 22492528 [PubMed - indexed for MEDLINE]

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AV-65, a novel Wnt/?-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model.

AV-65, a novel Wnt/?-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model.

Blood Cancer J. 2011 Nov;1(11):e43

Authors: Yao H, Ashihara E, Strovel JW, Nakagawa Y, Kuroda J, Nagao R, Tanaka R, Yokota A, Takeuchi M, Hayashi Y, Shimazaki C, Taniwaki M, Strand K, Padia J, Hirai H, Kimura S, Maekawa T

Abstract
Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that ?-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100?000 small-molecule chemical compounds for novel Wnt/?-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished ?-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

PMID: 22829079 [PubMed - in process]

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On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

On-Bead Screens Sample Narrower Affinity Ranges of Protein-Ligand Interactions Compared to Equivalent Solution Assays.

Chemphyschem. 2012 Jul 24;

Authors: Hintersteiner M, Buehler C, Auer M

PMID: 22829563 [PubMed - as supplied by publisher]

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Wednesday, July 25, 2012

Fluorine- and rhenium-containing geldanamycin derivatives as leads for the development of molecular probes for imaging Hsp90.

Fluorine- and rhenium-containing geldanamycin derivatives as leads for the development of molecular probes for imaging Hsp90.

Org Biomol Chem. 2012 Jul 24;

Authors: Wuest F, Bouvet V, Mai B, Lapointe P

Abstract
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone responsible for protein quality control in cells. Hsp90 has been shown to be overexpressed in many human cancers. This has prompted extensive research on Hsp90 inhibitors as novel anticancer agents and, more recently, the development of molecular probes for imaging Hsp90 expression in vivo. This work describes the development of various fluorine-containing and rhenium-containing geldanamycin derivatives as leads for the development of corresponding (18)F-labeled and (99m)Tc-labeled PET and SPECT probes for molecular imaging of Hsp90 expression. All compounds were evaluated in an in vitro ATPase activity assay using Hsp90 isoform Hsp82p. Fluorobenzoylated geldanamycin derivative displayed comparable inhibitory potency like parent compound geldanamycin.

PMID: 22825378 [PubMed - as supplied by publisher]

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ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity.

ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity.

Cell Death Dis. 2012;3:e253

Authors: Shao Y, Aplin AE

Abstract
B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro-apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ?8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells harboring mutant B-RAF. In this study, we show that Bmf is regulated at the post-translational level by mutant B-RAF-MEK-ERK2 signaling. Extracellular signal-regulated kinase (ERK2) directly phosphorylates Bmf on serine 74 and serine 77 residues with serine 77 being the predominant site. In addition, serine 77 phosphorylation reduces Bmf pro-apoptotic activity likely through a mechanism independent of altering Bmf localization to the mitochondria and/or interactions with dynein light chain 2 and the pro-survival proteins, B-cell lymphoma extra large, Bcl-2 and Mcl-1. These data identify a novel mode of regulation in Bmf that modulates its pro-apoptotic activity in mutant B-RAF tumor cells.

PMID: 22258404 [PubMed - indexed for MEDLINE]

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Natively unfolded state for engineering nanoscale fibrillar arrays.

Natively unfolded state for engineering nanoscale fibrillar arrays.

Macromol Biosci. 2012 Feb;12(2):195-201

Authors: Ryadnov MG, Cherny DI

Abstract
A generic rationale for the fabrication of high aspect ratio fibrillar nanoscale arrays is described. The design emulates an intermittence effect observed for ?-structured ?-synunclein fibrils, reported herein, in a structurally unrelated ?-helical fiber. The generated nanoarrays are composed of periodic nanosized segments separated at uniform distances of unfolded regions. These regions can be targeted for conformational binding and refolding with metal nanoparticle-peptide conjugates for the conversion of fibrillar arrays into nanoparticle arrays. The introduced concept opens new strategies for engineering novel nanoscale materials and devices.

PMID: 22147495 [PubMed - indexed for MEDLINE]

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ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity.

ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity.

Cell Death Dis. 2012;3:e253

Authors: Shao Y, Aplin AE

PMID: 22258404 [PubMed - indexed for MEDLINE]

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Role of resveratrol-induced CD11b(+) Gr-1(+) myeloid derived suppressor cells (MDSCs) in the reduction of CXCR3(+) T cells and amelioration of chronic colitis in IL-10(-/-) mice.

Role of resveratrol-induced CD11b(+) Gr-1(+) myeloid derived suppressor cells (MDSCs) in the reduction of CXCR3(+) T cells and amelioration of chronic colitis in IL-10(-/-) mice.

Brain Behav Immun. 2012 Jan;26(1):72-82

Authors: Singh UP, Singh NP, Singh B, Hofseth LJ, Taub DD, Price RL, Nagarkatti M, Nagarkatti PS

Abstract
Resveratrol, a naturally occurring polyphenol has received significant attention as a potent anti-inflammatory agent. Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce proinflammatory cytokines. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population characterized by the co-expression of CD11b(+) and Gr-1(+) and have long been known for their immunosuppressive function. We report that resveratrol effectively attenuated overall clinical scores as well as various pathological markers of colitis in IL-10(-/-) mice by down regulating Th1 responses. Resveratrol lessened the colitis-associated decrease in body weight and increased levels of serum amyloid A (SAA), CXCL10 and colon TNF-?, IL-6, RANTES, IL-12 and IL-1? concentrations. After resveratrol treatment, the percentage of CXCR3 expressing T cells was decreased in the spleen, mesenteric lymph nodes (MLN), and intestinal lamina propria (LP). However, the percentage and absolute numbers of CD11b(+) and Gr-1(+)cells in the lamina propria (LP) and spleen were increased after resveratrol treatment as compared with the vehicle treatment. Co-culture of resveratrol-induced CD11b(+) Gr-1(+) cells with T cells, attenuated T cell proliferation, and most importantly reduced IFN-? and GM-CSF production by LP derived T cells from vehicle treated IL-10(-/-) mice with chronic colitis. The current study suggests that administration of resveratrol into IL-10(-/-) mice induces immunosuppressive CD11b(+) Gr-1(+) MDSCs in the colon, which correlates with reversal of established chronic colitis, and down regulation of mucosal and systemic CXCR3(+) expressing effector T cells as well as inflammatory cytokines in the colon. The induction of immunosuppressive CD11b(+) Gr-1(+) cells by resveratrol during colitis is unique, and suggests an as-yet-unidentified mode of anti-inflammatory action of this plant polyphenol.

PMID: 21807089 [PubMed - indexed for MEDLINE]

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Tuesday, July 24, 2012

Development of a high-throughput screening method for LIM kinase 1 using a luciferase-based assay of ATP consumption.

Development of a high-throughput screening method for LIM kinase 1 using a luciferase-based assay of ATP consumption.

J Biomol Screen. 2012 Apr;17(4):460-8

Authors: Mezna M, Wong AC, Ainger M, Scott RW, Hammonds T, Olson MF

Abstract
Kinases are attractive drug targets because of the central roles they play in signal transduction pathways and human diseases. Their well-formed adenosine triphosphate (ATP)-binding pockets make ideal targets for small-molecule inhibitors. For drug discovery purposes, many peptide-based kinase assays have been developed that measure substrate phosphorylation using fluorescence-based readouts. However, for some kinases these assays may not be appropriate. In the case of the LIM kinases (LIMK), an inability to phosphorylate peptide substrates resulted in previous high-throughput screens (HTS) using radioactive labeling of recombinant cofilin protein as the readout. We describe the development of an HTS-compatible assay that measures relative ATP levels using luciferase-generated luminescence as a function of LIMK activity. The assay was inexpensive to perform, and proof-of-principle screening of kinase inhibitors demonstrated that compound potency against LIMK could be determined; ultimately, the assay was used for successful prosecution of automated HTS. Following HTS, the secondary assay format was changed to obtain more accurate measures of potency and mechanism of action using more complex (and expensive) assays. The luciferase assay nonetheless provides an inexpensive and reliable primary assay for HTS that allowed for the identification of LIMK inhibitors to initiate discovery programs for the eventual treatment of human diseases.

PMID: 22156225 [PubMed - indexed for MEDLINE]

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Lipopolysaccharide Induces Multinuclear Cell from RAW264.7 Line with Increased Phagocytosis Activity.

Lipopolysaccharide Induces Multinuclear Cell from RAW264.7 Line with Increased Phagocytosis Activity.

Biochem Biophys Res Commun. 2012 Jul 17;

Authors: Nakanishi-Matsui M, Yano S, Matsumoto N, Futai M

Abstract
Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria induces strong proinflammatory responses, including the release of cytokines and nitric oxide from macrophage. In this study, we found that a murine macrophage-derived line, RAW264.7, became multinuclear through cell-cell fusion after incubation with highly purified LPS or synthetic lipid A in the presence of Ca(2+). The same cell line is known to differentiate into multinuclear osteoclast, which expresses a specific proton pumping ATPase together with osteoclast markers on stimulation by the extracellular domain of receptor activator of nuclear factor kB ligand (Toyomura, T., Murata, Y., Yamamoto, A., Oka, T., Sun-Wada, G.-H., Wada, Y. and Futai, M. J. Biol. Chem. 278, 22023-22030, 2003). The LPS-induced multinuclear cells did not express osteoclast-specific enzymes including tartrate-resistant acid phosphatase and cathepsin K. During multinuclear cell formation, the cells internalized more and larger polystyrene beads (diameter 6 - 15 ?m) than mononuclear cells and osteoclasts. The internalized beads were located in lysosome-marker positive organelles, which were probably phagolysosomes. The LPS-induced multinuclear cell could be a good model system to study phagocytosis of large foreign bodies.

PMID: 22820190 [PubMed - as supplied by publisher]

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Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling.

Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling.

Development. 2011 Sep;138(18):3885-95

Authors: Kruithof-de Julio M, Alvarez MJ, Galli A, Chu J, Price SM, Califano A, Shen MM

Abstract
The signaling pathway for Nodal, a ligand of the TGF? superfamily, plays a central role in regulating the differentiation and/or maintenance of stem cell types that can be derived from the peri-implantation mouse embryo. Extra-embryonic endoderm stem (XEN) cells resemble the primitive endoderm of the blastocyst, which normally gives rise to the parietal and the visceral endoderm in vivo, but XEN cells do not contribute efficiently to the visceral endoderm in chimeric embryos. We have found that XEN cells treated with Nodal or Cripto (Tdgf1), an EGF-CFC co-receptor for Nodal, display upregulation of markers for visceral endoderm as well as anterior visceral endoderm (AVE), and can contribute to visceral endoderm and AVE in chimeric embryos. In culture, XEN cells do not express Cripto, but do express the related EGF-CFC co-receptor Cryptic (Cfc1), and require Cryptic for Nodal signaling. Notably, the response to Nodal is inhibited by the Alk4/Alk5/Alk7 inhibitor SB431542, but the response to Cripto is unaffected, suggesting that the activity of Cripto is at least partially independent of type I receptor kinase activity. Gene set enrichment analysis of genome-wide expression signatures generated from XEN cells under these treatment conditions confirmed the differing responses of Nodal- and Cripto-treated XEN cells to SB431542. Our findings define distinct pathways for Nodal and Cripto in the differentiation of visceral endoderm and AVE from XEN cells and provide new insights into the specification of these cell types in vivo.

PMID: 21862554 [PubMed - indexed for MEDLINE]

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Synthetic Procedure for N-Fmoc Amino Acyl-N-Sulfanylethylaniline Linker as Crypto-Peptide Thioester Precursor with Application to Native Chemical Ligation.

Synthetic Procedure for N-Fmoc Amino Acyl-N-Sulfanylethylaniline Linker as Crypto-Peptide Thioester Precursor with Application to Native Chemical Ligation.

J Org Chem. 2012 Jul 20;

Authors: Sakamoto K, Sato K, Shigenaga A, Tsuji K, Tsuda S, Hibino H, Nishiuchi Y, Otaka A

Abstract
N-Sulfanylethylanilide (SEAlide) peptides 1, obtainable using Fmoc-based solid-phase peptide synthesis (Fmoc SPPS), function as crypto-thioesters in native chemical ligation (NCL), yielding a wide variety of peptides/proteins. Their acylating potential with N-terminal cysteinyl peptides 2 can be tuned by the presence or absence of phosphate salts, leading to one-pot/multi-fragment ligation, operating under kinetically controlled conditions. SEAlide peptides have already been shown to be promising for use in protein synthesis; however, a widely applicable method for the synthesis of N-Fmoc amino acyl-N-sulfanylethylaniline linkers 4, required for the preparation of SEAlide peptides, is unavailable. The present study addresses the development of efficient condensation protocols of 20 naturally occurring amino acid derivatives to the N-sulfanylethylaniline linker 5. N-Fmoc amino acyl aniline linkers 4 of practical use in NCL chemistry, except in the case of the proline- or aspartic acid-containing linker, were successfully synthesized by coupling of POCl3- or SOCl2-activated Fmoc amino acid derivatives with sodium anilide species 6, without accompanying racemization and loss of side-chain protection. Furthermore, SEAlide peptides 7 possessing various C-terminal amino acids (Gly, His, Phe, Ala, Asn, Ser, Glu and Val) were shown to be of practical use in NCL chemistry.

PMID: 22816612 [PubMed - as supplied by publisher]

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Cyclotide synthesis and supply: from plant to bioprocess.

Cyclotide synthesis and supply: from plant to bioprocess.

Biopolymers. 2010;94(5):602-10

Authors: D�rnenburg H

Abstract
Cyclotides are disulfide-rich miniproteins with a circular backbone and a knotted arrangement ofdisulfide bonds. Because these plant-derived peptides are resistant to degradation and exhibit a diverse range of bioactivity they have become important agronomic and industrial objectives. They belong to a group of compounds with low market volume and high price that are poorly processed by microorganisms, are too complex for economic chemical synthesis, and thus are valuable candidates for the synthesis in plant cell bioprocesses. This review highlights current research aimed at production routes of cyclotides in Oldenlandia affinis plantlets and cell cultures, and summarizes recent advances in bioprocessing aspects, with particular emphasis on the development of suitable bioreactor configurations for plant cell culture-based processes, the optimization of culture environments as a powerful means to improve yields, bioreactor operational modes, and trends in protein recovery.

PMID: 20564040 [PubMed - indexed for MEDLINE]

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Monday, July 23, 2012

Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV.

Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV.

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5150-6

Authors: Manchester JI, Dussault DD, Rose JA, Boriack-Sjodin PA, Uria-Nickelsen M, Ioannidis G, Bist S, Fleming P, Hull KG

Abstract
We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56?M. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.

PMID: 22814212 [PubMed - in process]

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The KCNJ11 E23K polymorphism and progression of glycaemia in Southern Chinese: a long-term prospective study.

The KCNJ11 E23K polymorphism and progression of glycaemia in Southern Chinese: a long-term prospective study.

PLoS One. 2011;6(12):e28598

Authors: Cheung CY, Tso AW, Cheung BM, Xu A, Fong CH, Ong KL, Law LS, Wat NM, Janus ED, Sham PC, Lam KS

Abstract
CONTEXT: The KCNJ11 E23K variant is associated with type 2 diabetes mellitus (T2DM) in cross-sectional studies, but conflicting findings have been reported from prospective studies.
OBJECTIVE: This study aimed to evaluate whether the E23K variant could predict glycaemic progression in a Southern Chinese population.
METHODS/PRINCIPAL FINDINGS: We performed a long-term prospective study on 1912 subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS). The KCNJ11 E23K variant was associated with the progression to prediabetes after a median interval of 12 years on multinomial logistic regression analysis, even after adjustment for traditional risk factors (OR 1.29, P(age, sex, BMI and fasting plasma glucose [FPG] adjusted)?=?0.02). Based on Cox proportional hazard regression analysis, the E23K variant also predicted incident prediabetes (HR 1.18, P(age, sex, BMI and FPG adjusted)=?0.021). However, E23K was not associated with the progression to T2DM in either multinomial or Cox regression analysis, and the association of E23K with glycaemic progression to either prediabetes or T2DM was significant only in unadjusted Cox regression analysis (P?=?0.039). In a meta-analysis of eight prospective studies including our own, involving 15680 subjects, the E23K variant was associated with incident T2DM (fixed effect: OR 1.10, P?=?4�10(-3); random effect: OR 1.11, P?=?0.035).
CONCLUSIONS: Our study has provided supporting evidence for the role of the E23K variant in glycaemic progression in Chinese, with its effect being more evident in the early stage of T2DM, as the subjects progressed from normal glucose tolerance to prediabetes.

PMID: 22163043 [PubMed - indexed for MEDLINE]

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Role of angiotensin II in the periovulatory epidermal growth factor-like cascade in bovine granulosa cells in vitro.

Role of angiotensin II in the periovulatory epidermal growth factor-like cascade in bovine granulosa cells in vitro.

Biol Reprod. 2011 Dec;85(6):1167-74

Authors: Portela VM, Zamberlam G, Gon�alves PB, de Oliveira JF, Price CA

Abstract
Angiotensin II (AGT-2) induces follicular prostaglandin release in a number of species and ovulation in rabbits. Conversely, AGT-2 antagonists block ovulation in cattle. To determine the mechanism of action of AGT-2, we used a bovine granulosa cell model in which luteinizing hormone (LH) increased the expression of genes essential for ovulation in a time- and dose-dependent manner. The addition of AGT-2 to LH-stimulated cells significantly increased abundance of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA and protein, whereas AGT-2 alone had no effect. Upstream of PTGS2, AGT-2 increased abundance of mRNA encoding the epidermal growth factor-like ligands amphiregulin (AREG) and epiregulin (EREG) at 6 h posttreatment and abundance of a disintegrin and metalloprotease 17 (ADAM17), a sheddase, within 3 h of treatment. Inhibiting sheddase activity abolished the stimulatory effect of AGT-2 on AREG, EREG, and PTGS2 mRNA. The addition of selective AGT-2 antagonists to cells stimulated with LH plus AGT-2 demonstrated that AGT-2 did not act through the type 1 receptor and did not increase mitogen-activated protein kinase 3/1 phosphorylation. Combined with previous data from studies in vitro, we conclude that AGT-2 is an essential cofactor for LH in the early increase of ADAM expression/activity that induces the cascade of events leading to ovulation.

PMID: 21849708 [PubMed - indexed for MEDLINE]

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