Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

The aryl hydrocarbon receptor (AHR) is a major transcription factor regulated by different mechanisms. The classical view of AHR activation by xenobiotics needs to be amended by recent findings on the regulation of AHR by endogenous ligands and by crosstalk with other signaling pathways. In the cytosol the AHR recruits a large number of binding partners, including HSP90, p23, XAP2 and the ubiquitin ligases cullin 4B and CHIP. Furthermore, XAP2 binds the cyclic nucleotide phosphodiesterases PDE2A and PDE4A5. PDE2A inhibits nuclear translocation of AHR suggesting an important regulatory role of cyclic nucleotides in AHR trafficking. Signaling involving cAMP is organized in subcellular compartments and a distinct cAMP compartment might be required for proper AHR mobility and function. We conclude that the AHR complex integrates ligand binding and cyclic nucleotide signaling to generate an adequate transcriptional response

PDE2A interacts with XAP2

Phosphodiesterase type 2A (PDE2A) hydrolyzes cyclic nucleotides cAMP and cGMP, thus efficiently controlling cNMP-dependent signaling pathways. PDE2A is composed of an amino-terminal region, two regulatory GAF domains, and a catalytic domain. Cyclic nucleotide hydrolysis is known to be activated by cGMP binding to GAF-B; however, other mechanisms may operate to fine-tune local cyclic nucleotide levels. In a yeast two-hybrid screening we identified XAP2, a crucial component of the aryl hydrocarbon receptor (AhR) complex, as a major PDE2A-interacting protein. We mapped the XAP2 binding site to the GAF-B domain of PDE2A. PDE assays with purified proteins showed that XAP2 binding does not change the enzymatic activity of PDE2A. To analyze whether PDE2A could affect the function of XAP2, we studied nuclear translocation of AhR, i.e. the master transcription factor controlling the expression of multiple detoxification genes. Notably, regulation of AhR target gene expression is initiated by tetrachlorodibenzodioxin (TCDD) binding to AhR and by a poorly understood cAMP-dependent pathway followed by the translocation of AhR from the cytosol into the nucleus. Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes. Furthermore, PDE2A attenuated TCDD-induced transcription in reporter gene assays. We conclude that XAP2 targets PDE2A to the AhR complex, thereby restricting AhR mobility, possibly by a local reduction of cAMP levels. Our results provide first insights into the elusive cAMP-dependent regulation of AhR.Deutsche Forschungsgemeinschaf

Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor

Phosphodiesterase type 2A (PDE2A) hydrolyzes cyclic nucleotides cAMP and cGMP, thus efficiently controlling cNMP-dependent signaling pathways. PDE2A is composed of an amino-terminal region, two regulatory GAF domains, and a catalytic domain. Cyclic nucleotide hydrolysis is known to be activated by cGMP binding to GAF-B; however, other mechanisms may operate to fine-tune local cyclic nucleotide levels. In a yeast two-hybrid screening we identified XAP2, a crucial component of the aryl hydrocarbon receptor (AhR) complex, as a major PDE2A-interacting protein. We mapped the XAP2 binding site to the GAF-B domain of PDE2A. PDE assays with purified proteins showed that XAP2 binding does not change the enzymatic activity of PDE2A. To analyze whether PDE2A could affect the function of XAP2, we studied nuclear translocation of AhR, i.e. the master transcription factor controlling the expression of multiple detoxification genes. Notably, regulation of AhR target gene expression is initiated by tetrachlorodibenzodioxin (TCDD) binding to AhR and by a poorly understood cAMP-dependent pathway followed by the translocation of AhR from the cytosol into the nucleus. Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes. Furthermore, PDE2A attenuated TCDD-induced transcription in reporter gene assays. We conclude that XAP2 targets PDE2A to the AhR complex, thereby restricting AhR mobility, possibly by a local reduction of cAMP levels. Our results provide first insights into the elusive cAMP-dependent regulation of AhR

Search for the Standard Model Higgs boson in the decay channel H→ZZ(*)→4ℓ with the ATLAS detector

A search for the Standard Model Higgs boson in the decay channel H -> ZZ(()*()) l(+)l(-)l'l'(-), where l = e, mu, is presented. Proton-proton collision data at root s = 7 TeV recorded with the ATLAS detector and corresponding to an average integrated luminosity of 2.1 fb(-1) are compared to the Standard Model expectations. Upper limits on the production cross section of a Standard Model Higgs boson with a mass between 110 and 600 GeV are derived. The observed (expected) 95% confidence level upper limit on the production cross section for a Higgs boson with a mass of 194 GeV, the region with the best expected sensitivity for this search, is 0.99 (1.01) times the Standard Model prediction. The Standard Model Higgs boson is excluded at 95% confidence level in the mass ranges 191-197, 199-200 and 214-224 GeV. (C) 2011 CERN. Published by Elsevier B.V. All rights reserved

Search for the Standard Model Higgs boson in the decay channel H -> ZZ(()*()) -> 4l with the ATLAS detector

A search for the Standard Model Higgs boson in the decay channel H→ZZ(*)→ℓ+ℓ-ℓ'+ℓ'-, where ℓ=e, μ, is presented. Proton-proton collision data at s=7TeV recorded with the ATLAS detector and corresponding to an average integrated luminosity of 2.1fb-1 are compared to the Standard Model expectations. Upper limits on the production cross section of a Standard Model Higgs boson with a mass between 110 and 600GeV are derived. The observed (expected) 95% confidence level upper limit on the production cross section for a Higgs boson with a mass of 194 GeV, the region with the best expected sensitivity for this search, is 0.99 (1.01) times the Standard Model prediction. The Standard Model Higgs boson is excluded at 95% confidence level in the mass ranges 191-197, 199-200 and 214-224 GeV. © 2011 CERN

Search for new physics in the dijet mass distribution using 1 fb⁻¹ of <i>pp</i> collision data at &#8730;s=7 TeV collected by the ATLAS detector

Invariant mass distributions of jet pairs (dijets) produced in LHC proton–proton collisions at a centre-of-mass energy &#8730;s=7  TeV have been studied using a data set corresponding to an integrated luminosity of 1.0 fb&lt;sup&gt;-1&lt;/sup&gt;recorded in 2011 by ATLAS. Dijet masses up to &#8764;4 TeV are observed in the data, and no evidence of resonance production over background is found. Limits are set at 95% C.L. for several new physics hypotheses: excited quarks are excluded for masses below 299 TeV, axigluons are excluded for masses below 3.32 TeV, and colour octet scalar resonances are excluded for masses below 1.92 TeV

Search for new physics in the dijet mass distribution using 1 fb(-1) of pp collision data at root s=7 TeV collected by the ATLAS detector

Invariant mass distributions of jet pairs (dijets) produced in LHC proton-proton collisions at a centre-of-mass energy root s = 7 TeV have been studied using a data set corresponding to an integrated luminosity of 1.0 fb(-1) recorded in 2011 by ATLAS. Dijet masses up to similar to 4 TeV are observed in the data, and no evidence of resonance production over background is found. Limits are set at 95% C.L. for several new physics hypotheses: excited quarks are excluded for masses below 299 TeV, axigluons are excluded for masses below 3.32 TeV. and colour octet scalar resonances are excluded for masses below 1.92 TeV. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved

Searches for supersymmetry with the ATLAS detector using final states with two leptons and missing transverse momentum in root s=7 TeV proton-proton collisions

Results of three searches are presented for the production of supersymmetric particles decaying into final states with missing transverse momentum and exactly two isolated leptons, e or mu. The analysis uses a data sample collected during the first half of 2011 that corresponds to a total integrated luminosity of 1 fb(-1) of root s = 7 TeV proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider. Opposite-sign and same-sign dilepton events are separately studied, with no deviations from the Standard Model expectation observed. Additionally, in opposite-sign events, a search is made for an excess of same-flavour over different-flavour lepton pairs. Effective production cross sections in excess of 9.9 fb for opposite-sign events containing supersymmetric particles with missing transverse momentum greater than 250 GeV are excluded at 95% CL For same-sign events containing supersymmetric particles with missing transverse momentum greater than 100 GeV, effective production cross sections in excess of 14.8 fb are excluded at 95% CL The latter limit is interpreted in a simplified electroweak gaugino production model excluding chargino masses up to 200 GeV, under the assumption that slepton decay is dominant. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved