The Experts below are selected from a list of 47634 Experts worldwide ranked by ideXlab platform
Hf Berntsen - One of the best experts on this subject based on the ideXlab platform.
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Human blood-based exposure levels of persistent organic pollutant (POP) mixtures antagonise androgen receptor Transactivation and translocation
'Elsevier BV', 2019Co-Authors: Mccomb J, Ig Mills, Muller M, Hf Berntsen, Ke Zimmer, Ropstad E, Verhaegen S, Connolly LAbstract:INTRODUCTION:Human exposure to persistent organic pollutants (POPs) has been linked to genitourinary health-related conditions such as decreased sperm quality, hypospadias, and prostate cancer (PCa). Conventional risk assessment of POPs focuses on individual compounds. However, in real life, individuals are exposed to many compounds simultaneously. This might lead to combinatorial effects whereby the global effect of the mixture is different from the effect of the single elements or subgroups. POP mixtures may act as endocrine disruptors via the androgen receptor (AR) and potentially contribute to PCa development. AIM:To determine the endocrine disrupting activity of a POP mixture and sub-mixtures based upon exposure levels detected in a human Scandinavian population, on AR Transactivation and translocation in vitro. MATERIALS AND METHODS:The Total POP mixture combined 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br), chlorinated (Cl), Cl + Br, perfluorinated (PFAA), PFAA + Br, PFAA + Cl, ranging from 1/10× to 500× relative to what is found in human blood. Transactivation was measured by reporter gene assay (RGA) and translocation activity was measured by high content analysis (HCA), each using stably transfected AR model cell lines. RESULTS:No agonist activity in terms of Transactivation and translocation was detected for any POP mixtures. In the presence of testosterone the Cl + Br mixture at 100× and 500× blood level antagonised AR Transactivation, whereas the PFAA mixture at blood level increased AR Transactivation (P
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human blood based exposure levels of persistent organic pollutant pop mixtures antagonise androgen receptor Transactivation and translocation
Environment International, 2019Co-Authors: Jonathan Mccomb, Hf Berntsen, Ian G Mills, Marc Muller, Karin Elisabeth Zimmer, Erik Ropstad, Steven Verhaegen, Lisa ConnollyAbstract:Abstract Introduction Human exposure to persistent organic pollutants (POPs) has been linked to genitourinary health-related conditions such as decreased sperm quality, hypospadias, and prostate cancer (PCa). Conventional risk assessment of POPs focuses on individual compounds. However, in real life, individuals are exposed to many compounds simultaneously. This might lead to combinatorial effects whereby the global effect of the mixture is different from the effect of the single elements or subgroups. POP mixtures may act as endocrine disruptors via the androgen receptor (AR) and potentially contribute to PCa development. Aim To determine the endocrine disrupting activity of a POP mixture and sub-mixtures based upon exposure levels detected in a human Scandinavian population, on AR Transactivation and translocation in vitro. Materials and methods The Total POP mixture combined 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br), chlorinated (Cl), Cl + Br, perfluorinated (PFAA), PFAA + Br, PFAA + Cl, ranging from 1/10× to 500× relative to what is found in human blood. Transactivation was measured by reporter gene assay (RGA) and translocation activity was measured by high content analysis (HCA), each using stably transfected AR model cell lines. Results No agonist activity in terms of Transactivation and translocation was detected for any POP mixtures. In the presence of testosterone the Cl + Br mixture at 100× and 500× blood level antagonised AR Transactivation, whereas the PFAA mixture at blood level increased AR Transactivation (P Conclusion Taken together, some combinations of POP mixtures can interfere with AR translocation. However, in the Transactivation assay, these combinations did not affect gene Transactivation. Other POP combinations were identified here as modulators of AR-induced gene Transactivation without affecting AR translocation. Thus, to fully evaluate the effect of environmental toxins on AR signalling, both types of assays need to be applied.
Lisa Connolly - One of the best experts on this subject based on the ideXlab platform.
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human blood based exposure levels of persistent organic pollutant pop mixtures antagonise androgen receptor Transactivation and translocation
Environment International, 2019Co-Authors: Jonathan Mccomb, Hf Berntsen, Ian G Mills, Marc Muller, Karin Elisabeth Zimmer, Erik Ropstad, Steven Verhaegen, Lisa ConnollyAbstract:Abstract Introduction Human exposure to persistent organic pollutants (POPs) has been linked to genitourinary health-related conditions such as decreased sperm quality, hypospadias, and prostate cancer (PCa). Conventional risk assessment of POPs focuses on individual compounds. However, in real life, individuals are exposed to many compounds simultaneously. This might lead to combinatorial effects whereby the global effect of the mixture is different from the effect of the single elements or subgroups. POP mixtures may act as endocrine disruptors via the androgen receptor (AR) and potentially contribute to PCa development. Aim To determine the endocrine disrupting activity of a POP mixture and sub-mixtures based upon exposure levels detected in a human Scandinavian population, on AR Transactivation and translocation in vitro. Materials and methods The Total POP mixture combined 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br), chlorinated (Cl), Cl + Br, perfluorinated (PFAA), PFAA + Br, PFAA + Cl, ranging from 1/10× to 500× relative to what is found in human blood. Transactivation was measured by reporter gene assay (RGA) and translocation activity was measured by high content analysis (HCA), each using stably transfected AR model cell lines. Results No agonist activity in terms of Transactivation and translocation was detected for any POP mixtures. In the presence of testosterone the Cl + Br mixture at 100× and 500× blood level antagonised AR Transactivation, whereas the PFAA mixture at blood level increased AR Transactivation (P Conclusion Taken together, some combinations of POP mixtures can interfere with AR translocation. However, in the Transactivation assay, these combinations did not affect gene Transactivation. Other POP combinations were identified here as modulators of AR-induced gene Transactivation without affecting AR translocation. Thus, to fully evaluate the effect of environmental toxins on AR signalling, both types of assays need to be applied.
Ian G Mills - One of the best experts on this subject based on the ideXlab platform.
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human blood based exposure levels of persistent organic pollutant pop mixtures antagonise androgen receptor Transactivation and translocation
Environment International, 2019Co-Authors: Jonathan Mccomb, Hf Berntsen, Ian G Mills, Marc Muller, Karin Elisabeth Zimmer, Erik Ropstad, Steven Verhaegen, Lisa ConnollyAbstract:Abstract Introduction Human exposure to persistent organic pollutants (POPs) has been linked to genitourinary health-related conditions such as decreased sperm quality, hypospadias, and prostate cancer (PCa). Conventional risk assessment of POPs focuses on individual compounds. However, in real life, individuals are exposed to many compounds simultaneously. This might lead to combinatorial effects whereby the global effect of the mixture is different from the effect of the single elements or subgroups. POP mixtures may act as endocrine disruptors via the androgen receptor (AR) and potentially contribute to PCa development. Aim To determine the endocrine disrupting activity of a POP mixture and sub-mixtures based upon exposure levels detected in a human Scandinavian population, on AR Transactivation and translocation in vitro. Materials and methods The Total POP mixture combined 29 chemicals modelled on the exposure profile of a Scandinavian population and 6 sub-mixtures: brominated (Br), chlorinated (Cl), Cl + Br, perfluorinated (PFAA), PFAA + Br, PFAA + Cl, ranging from 1/10× to 500× relative to what is found in human blood. Transactivation was measured by reporter gene assay (RGA) and translocation activity was measured by high content analysis (HCA), each using stably transfected AR model cell lines. Results No agonist activity in terms of Transactivation and translocation was detected for any POP mixtures. In the presence of testosterone the Cl + Br mixture at 100× and 500× blood level antagonised AR Transactivation, whereas the PFAA mixture at blood level increased AR Transactivation (P Conclusion Taken together, some combinations of POP mixtures can interfere with AR translocation. However, in the Transactivation assay, these combinations did not affect gene Transactivation. Other POP combinations were identified here as modulators of AR-induced gene Transactivation without affecting AR translocation. Thus, to fully evaluate the effect of environmental toxins on AR signalling, both types of assays need to be applied.
Cunming Duan - One of the best experts on this subject based on the ideXlab platform.
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duplicated zebrafish insulin like growth factor binding protein 5 genes with split functional domains evidence for evolutionarily conserved igf binding nuclear localization and Transactivation activity
The FASEB Journal, 2010Co-Authors: Wei Dai, Yang Zhao, Hiroyasu Kamei, Jun Ding, Cunming DuanAbstract:Insulin-like growth factor binding protein (IGFBP)-5 is a secreted protein that binds to IGF and modulates IGF actions. IGFBP-5 is also found in the nucleus of mammalian cells and has Transactivation activity. The structural basis of this Transactivation activity and its role in mediating IGF-independent actions are not clear. Here we report that there are 2 igfbp-5 genes in zebrafish and other teleost fish. In zebrafish, igfbp-5a and -5b are expressed in spatially restricted, mostly nonoverlapping domains during early development. The IGF binding site is conserved in both zebrafish IGFBP-5s, and they are both secreted and capable of IGF binding. Both proteins contain a consensus bipartite nuclear localization signal and were found in the nucleus when introduced into cultured cells. Although zebrafish IGFBP-5b possesses Transactivation activity, zebrafish IGFBP-5a lacks this activity. Mutational analysis demonstrated that 2 unique amino acids in positions 22 and 56 of IGFBP-5a are responsible for its lack of Transactivation activity. These findings suggest that the duplicated zebrafish IGFBP-5s have evolved divergent regulatory mechanisms and distinct biological properties by partitioning of ancestral structural domains and provide new evidence for a conserved role of the IGF binding, nuclear localization, and Transactivation domain of this multifunctional IGFBP.—Dai, W., Kamei, H., Zhao, Y., Ding, J., Du, Z., Duan, C. Duplicated zebrafish insulin-like growth factor binding protein-5 genes with split functional domains: evidence for evolutionarily conserved IGF binding, nuclear localization, and Transactivation activity.
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several acidic amino acids in the n domain of insulin like growth factor binding protein 5 are important for its Transactivation activity
Journal of Biological Chemistry, 2006Co-Authors: Yang Zhao, Ping Yin, Leon A Bach, Cunming DuanAbstract:Insulin-like growth factor-binding protein (IGFBP)-5 is a secreted protein that binds to IGFs and modulates IGF actions. IGFBP-5 is also found in the nuclei of cultured cells and has Transactivation activity. Here we report the nuclear localization of endogenous IGFBP-5 in mouse embryonic skeletal cells. Chromatin immunoprecipitation experiments indicated that IGFBP-5 interacts with the nuclear histone-DNA complex. Using a series of deletion mutants, the Transactivation domain of IGFBP-5 was mapped to its N-terminal region. Intriguingly, the Transactivation activity of IGFBP-5 is masked by negative regulatory elements located in the L- and C-domains. Among the other IGFBPs, the N-domains of IGFBP-2 and -3 also had strong Transactivation activity, whereas those of IGFBP-1 and -6 had no activity. The IGFBP-4 N-domain had modest activity. Sequence analysis revealed several amino acids in the IGFBP-5 N-domain that are not present in IGFBP-1. The activities of mutants in which these residues were changed to the corresponding IGFBP-1 sequence were determined. Mutations that changed acidic residues to neutral residues (e.g. E8A, D11S, E12A, E30S/P31A, E43L, and E52A) or a polar to a basic residue (e.g. Q56R) significantly reduced Transactivation activity. The E8A/D11S/E12A triple mutant and E52A/Q56R double mutants showed further reduced activity. The combinatory mutants had essentially no Transactivation activity. Taken together, our results indicate that there are several conserved residues in the IGFBP-5 N-terminal region that are critical for Transactivation and that IGFBP-2 and -3 also have strong Transactivation activity in their N-domains.
Satoru Eguchi - One of the best experts on this subject based on the ideXlab platform.
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adam17 mediates epidermal growth factor receptor Transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin ii
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: Haruhiko Ohtsu, Gerald D. Frank, Hiroyuki Suzuki, Hidekatsu Nakashima, Eugen Brailoiu, Peter J Dempsey, Sadaharu Higuchi, Kunie Eguchi, Satoru EguchiAbstract:Background— Angiotensin II (Ang II) promotes growth of vascular smooth muscle cells (VSMCs) via epidermal growth factor (EGF) receptor (EGFR) Transactivation mediated through a metalloprotease-dependent shedding of heparin-binding EGF-like growth factor (HB-EGF). However, the identity of the metalloprotease responsible for this process remains unknown. Methods and Results— To identify the metalloprotease required for Ang II-induced EGFR Transactivation, primary cultured aortic VSMCs were infected with retrovirus encoding dominant negative (dn) mutant of ADAM10 or ADAM17. EGFR Transactivation induced by Ang II was inhibited in VSMCs infected with dnADAM17 retrovirus but not with dnADAM10 retrovirus. However, Ang II comparably stimulated intracellular Ca 2+ elevation and JAK2 tyrosine phosphorylation in these VSMCs. In addition, dnADAM17 inhibited HB-EGF shedding induced by Ang II in A10 VSMCs expressing the AT 1 receptor. Moreover, Ang II enhanced protein synthesis and cell volume in VSMCs infected with control retrovirus, but not in VSMCs infected with dnADAM17 retrovirus. Conclusion— ADAM17 activated by the AT 1 receptor is responsible for EGFR Transactivation and subsequent protein synthesis in VSMCs. These findings demonstrate a previously missing molecular mechanism by which Ang II promotes vascular remodeling.
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adams as mediators of egf receptor Transactivation by g protein coupled receptors
American Journal of Physiology-cell Physiology, 2006Co-Authors: Haruhiko Ohtsu, Peter J Dempsey, Satoru EguchiAbstract:A disintegrin and metalloprotease (ADAM) is a membrane-anchored metalloprotease implicated in the ectodomain shedding of cell surface proteins, including the ligands for epidermal growth factor (EGF) receptors (EGFR)/ErbB. It has been well documented that the Transactivation of the EGFR plays critical roles for many cellular functions, such as proliferation and migration mediated through multiple G protein-coupled receptors (GPCRs). Recent accumulating evidence has suggested that ADAMs are the key metalloproteases activated by several GPCR agonists to produce a mature EGFR ligand leading to the EGFR Transactivation. In this review, we describe the current knowledge on ADAMs implicated in mediating EGFR Transactivation. The major focus of the review will be on the possible upstream mechanisms of ADAM activation by GPCRs as well as downstream signal transduction and the pathophysiological significances of ADAM-dependent EGFR Transactivation.
