The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Amy S Lee - One of the best experts on this subject based on the ideXlab platform.
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atf6 as a transcription activator of the endoplasmic reticulum stress element thapsigargin stress induced changes and synergistic interactions with nf y and yy1
Molecular and Cellular Biology, 2000Co-Authors: Peter Baumeister, Shengzhan Luo, Binayak Roy, Trevor Phan, Dolly M Foti, Amy S LeeAbstract:ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism of grp78 induction by ATF6 in cells subjected to ER Calcium Depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress-induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane domain, is primarily associated with the perinuclear region. Upon Tg stress, the ATF6 protein level dropped initially but quickly recovered with the additional appearance of a faster-migrating form. This new form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence. Optimal ATF6 stimulation requires at least two copies of the ERSE and the integrity of the tripartite structure of the ERSE. Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility. In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity. The ERSE stimulatory activity of ATF6 exhibits properties distinct from those of human Ire1p, an upstream regulator of the mammalian unfolded protein response. The requirement for a high-affinity NF-Y site for ATF6 but not human Ire1p activity suggests that they stimulate the ERSE through diverse pathways.
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the mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress inducible complex
Nucleic Acids Research, 1999Co-Authors: Binayak Roy, Amy S LeeAbstract:When mammalian cells are subjected to Calcium Depletion stress or protein glycosylation block, the transcription of a family of glucose-regulated protein (GRP) genes encoding endoplasmic reticulum (ER) chaperones is induced to high levels. The consensus mammalian ER stress response element (ERSE) conserved among grp promoters consists of a tripartite structure CCAAT(N9)CCACG, with N being a strikingly GC-rich region of 9 bp. The ERSE, in duplicate copies, can confer full stress inducibility to a heterologous promoter in a sequence-specific but orientation-independent manner. In addition to CBF/NF-Y and YY1 binding to the CCAAT and CCACG motifs, respectively, we further discovered that an ER stress-inducible complex (ERSF) from HeLa nuclear extract binds specifically to the ERSE. Strikingly, the interaction of the ERSF with the ERSE requires a conserved GGC motif within the 9 bp region. Since mutation of the GGC triplet sequence also results in loss of stress inducibility, specific sequence within the 9 bp region is an integral part of the tripartite structure. Finally, correlation of factor binding with stress inducibility reveals that ERSF binding to the ERSE alone is not sufficient; full stress inducibility requires integrity of the CCAAT, GGC and CCACG sequence motifs, as well as precise spacing among these sites.
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Calcium sensitive transcriptional activation of the proximal ccaat regulatory element of the grp78 bip promoter by the human nuclear factor cbf nf y
Journal of Biological Chemistry, 1996Co-Authors: Binayak Roy, Amy S LeeAbstract:Abstract Transcription of the gene encoding GRP78/BiP, a Calcium-binding molecular chaperone localized in the endoplasmic reticulum, is induced in mammalian cells through gradual Depletion of the intracellular Calcium stores. The multimeric CCAAT binding factor, CBF/NF-Y, binds to the most proximal CCAAT regulatory element (C1) of the grp78 promoter required for both basal level expression and stress response. Using an in vitro transcription system, we show through factor competition and immunoDepletion that the grp78 C1-mediated enhancement of transcription requires primarily CBF. Correlating with the previous observation that CBF binding to the 78C1 site is enhanced by EGTA and EDTA, these divalent cation chelators specifically stimulate 78C1-directed transcription. In contrast, increasing amounts of Calcium ions are inhibitory. These results provide evidence that CBF is functionally important in transactivating the grp78 C1 transcriptional activity, and suggest a possible mechanism by which grp78 transcription is stimulated by Calcium Depletion. We further discovered that in addition to binding CBF, both the 78C1 element and the CBF binding site of the α2(I) collagen promoter interact weakly with the multifunctional transcription factor YY1. Our studies show that the binding sites for CBF and YY1 are distinct for the two promoter sites, suggesting that YY1 and other interacting factors could exert differential effects on individual promoters bearing the same CBF site.
Thomas G. Huntington - One of the best experts on this subject based on the ideXlab platform.
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Calcium Depletion in a Southeastern United States forest ecosystem
Soil Science Society of America Journal, 2000Co-Authors: Thomas G. Huntington, Richard P. Hooper, Chris E. Johnson, Brent T. Aulenbach, R. Cappellato, Alex E. BlumAbstract:U.S. forests has been suggested in earlier reviews (Mann et al., 1988; Federer et al., 1989; Shortle and Bondietti, Forest soil Ca Depletion through leaching and vegetation uptake 1992) and modeling studies (Binkley et al., 1989b), but may threaten long-term sustainability of forest productivity in the few studies have quantified inputs and outputs in relasoutheastern USA. This study was conducted to assess Ca pools and fluxes in a representative southern Piedmont forest to determine the tion to soil reserves. soil Ca Depletion rate. Soil Ca storage, Ca inputs in atmospheric Southeastern forest soils are especially prone to Ca deposition, and outputs in soil leaching and vegetation uptake were Depletion for several reasons. First, these soils generally investigated at the Panola Mountain Research Watershed (PMRW) developed in base-poor igneous and metamorphic rocks. near Atlanta, GA. Average annual outputs of 12.3 kg ha 21 yr 21 in Second, these soils typically are old, having weathered uptake into merchantable wood and 2.71 kg ha 21 yr 21 soil leaching in place for several hundred thousand to 2 million years, exceeded inputs in atmospheric deposition of 2.24 kg ha 21 yr 21
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The potential for Calcium Depletion in forest ecosystems of southeastern United States: Review and analysis
Global Biogeochemical Cycles, 2000Co-Authors: Thomas G. HuntingtonAbstract:Biogeochemical mass balance assessments of Calcium status in southeastern forests indicate that losses through harvesting and soil leaching often exceed inputs from atmospheric deposition and weathering. Many forest soils of the southeastern United States are particularly sensitive because these soils and the underlying saprolite from which these soils are derived are largely depleted of weatherable Calcium. At most of the intensively studied sites in the southeastern United States, it is estimated that Calcium Depletion has already reduced or will likely reduce exchangeable soil Calcium reserves to less than the estimated requirement for a merchantable forest stand in 150 years or less. At most sites, Calcium uptake into merchantable wood equals or exceeds soil leaching losses. Chronic atmospheric deposition of sulfate and nitrate and declining atmospheric deposition of Calcium are likely to accelerate Calcium Depletion. The southeastern U.S. regional distribution of soil Calcium pools and Calcium fluxes (deposition and uptake in merchantable wood) indicates that the Depletion status of the intensively studied sites is representative of a substantially larger area. Where weathering inputs are insufficient to replace leaching and uptake losses, there is a potential for a regional problem in forest nutrition over the long term.
Binayak Roy - One of the best experts on this subject based on the ideXlab platform.
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atf6 as a transcription activator of the endoplasmic reticulum stress element thapsigargin stress induced changes and synergistic interactions with nf y and yy1
Molecular and Cellular Biology, 2000Co-Authors: Peter Baumeister, Shengzhan Luo, Binayak Roy, Trevor Phan, Dolly M Foti, Amy S LeeAbstract:ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism of grp78 induction by ATF6 in cells subjected to ER Calcium Depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress-induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane domain, is primarily associated with the perinuclear region. Upon Tg stress, the ATF6 protein level dropped initially but quickly recovered with the additional appearance of a faster-migrating form. This new form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence. Optimal ATF6 stimulation requires at least two copies of the ERSE and the integrity of the tripartite structure of the ERSE. Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility. In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity. The ERSE stimulatory activity of ATF6 exhibits properties distinct from those of human Ire1p, an upstream regulator of the mammalian unfolded protein response. The requirement for a high-affinity NF-Y site for ATF6 but not human Ire1p activity suggests that they stimulate the ERSE through diverse pathways.
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the mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress inducible complex
Nucleic Acids Research, 1999Co-Authors: Binayak Roy, Amy S LeeAbstract:When mammalian cells are subjected to Calcium Depletion stress or protein glycosylation block, the transcription of a family of glucose-regulated protein (GRP) genes encoding endoplasmic reticulum (ER) chaperones is induced to high levels. The consensus mammalian ER stress response element (ERSE) conserved among grp promoters consists of a tripartite structure CCAAT(N9)CCACG, with N being a strikingly GC-rich region of 9 bp. The ERSE, in duplicate copies, can confer full stress inducibility to a heterologous promoter in a sequence-specific but orientation-independent manner. In addition to CBF/NF-Y and YY1 binding to the CCAAT and CCACG motifs, respectively, we further discovered that an ER stress-inducible complex (ERSF) from HeLa nuclear extract binds specifically to the ERSE. Strikingly, the interaction of the ERSF with the ERSE requires a conserved GGC motif within the 9 bp region. Since mutation of the GGC triplet sequence also results in loss of stress inducibility, specific sequence within the 9 bp region is an integral part of the tripartite structure. Finally, correlation of factor binding with stress inducibility reveals that ERSF binding to the ERSE alone is not sufficient; full stress inducibility requires integrity of the CCAAT, GGC and CCACG sequence motifs, as well as precise spacing among these sites.
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Calcium sensitive transcriptional activation of the proximal ccaat regulatory element of the grp78 bip promoter by the human nuclear factor cbf nf y
Journal of Biological Chemistry, 1996Co-Authors: Binayak Roy, Amy S LeeAbstract:Abstract Transcription of the gene encoding GRP78/BiP, a Calcium-binding molecular chaperone localized in the endoplasmic reticulum, is induced in mammalian cells through gradual Depletion of the intracellular Calcium stores. The multimeric CCAAT binding factor, CBF/NF-Y, binds to the most proximal CCAAT regulatory element (C1) of the grp78 promoter required for both basal level expression and stress response. Using an in vitro transcription system, we show through factor competition and immunoDepletion that the grp78 C1-mediated enhancement of transcription requires primarily CBF. Correlating with the previous observation that CBF binding to the 78C1 site is enhanced by EGTA and EDTA, these divalent cation chelators specifically stimulate 78C1-directed transcription. In contrast, increasing amounts of Calcium ions are inhibitory. These results provide evidence that CBF is functionally important in transactivating the grp78 C1 transcriptional activity, and suggest a possible mechanism by which grp78 transcription is stimulated by Calcium Depletion. We further discovered that in addition to binding CBF, both the 78C1 element and the CBF binding site of the α2(I) collagen promoter interact weakly with the multifunctional transcription factor YY1. Our studies show that the binding sites for CBF and YY1 are distinct for the two promoter sites, suggesting that YY1 and other interacting factors could exert differential effects on individual promoters bearing the same CBF site.
Ying Maggie Chen - One of the best experts on this subject based on the ideXlab platform.
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discovery of endoplasmic reticulum Calcium stabilizers to rescue er stressed podocytes in nephrotic syndrome
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Sun Ji Park, Fumihiko Urano, Yeawon Kim, Shyh Ming Yang, Mark J Henderson, Wei Yang, Maria Lindahl, Ying Maggie ChenAbstract:Emerging evidence has established primary nephrotic syndrome (NS), including focal segmental glomerulosclerosis (FSGS), as a primary podocytopathy. Despite the underlying importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of NS, no treatment currently targets the podocyte ER. In our monogenic podocyte ER stress-induced NS/FSGS mouse model, the podocyte type 2 ryanodine receptor (RyR2)/Calcium release channel on the ER was phosphorylated, resulting in ER Calcium leak and cytosolic Calcium elevation. The altered intracellular Calcium homeostasis led to activation of Calcium-dependent cytosolic protease calpain 2 and cleavage of its important downstream substrates, including the apoptotic molecule procaspase 12 and podocyte cytoskeletal protein talin 1. Importantly, a chemical compound, K201, can block RyR2-Ser2808 phosphorylation-mediated ER Calcium Depletion and podocyte injury in ER-stressed podocytes, as well as inhibit albuminuria in our NS model. In addition, we discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) can revert defective RyR2-induced ER Calcium leak, a bioactivity for this ER stress-responsive protein. Thus, podocyte RyR2 remodeling contributes to ER stress-induced podocyte injury. K201 and MANF could be promising therapies for the treatment of podocyte ER stress-induced NS/FSGS.
Christopher C Glembotski - One of the best experts on this subject based on the ideXlab platform.
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mesencephalic astrocyte derived neurotrophic factor protects the heart from ischemic damage and is selectively secreted upon sarco endoplasmic reticulum Calcium Depletion
Journal of Biological Chemistry, 2012Co-Authors: Christopher C Glembotski, Donna J Thuerauf, Chengqun Huang, John A Vekich, Roberta A Gottlieb, Shirin DoroudgarAbstract:The endoplasmic reticulum (ER) stress protein mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to protect cells from stress-induced cell death before and after its secretion; however, the conditions under which it is secreted are not known. Accordingly, we examined the mechanism of MANF release from cultured ventricular myocytes and HeLa cells, both of which secrete proteins via the constitutive pathway. Although the secretion of proteins via the constitutive pathway is not known to increase upon changes in intracellular Calcium, MANF secretion was increased within 30 min of treating cells with compounds that deplete sarcoplasmic reticulum (SR)/ER Calcium. In contrast, secretion of atrial natriuretic factor from ventricular myocytes was not increased by SR/ER Calcium Depletion, suggesting that not all secreted proteins exhibit the same characteristics as MANF. We postulated that SR/ER Calcium Depletion triggered MANF secretion by decreasing its retention. Consistent with this were co-immunoprecipitation and live cell, zero distance, photo affinity cross-linking, demonstrating that, in part, MANF was retained in the SR/ER via its Calcium-dependent interaction with the SR/ER-resident protein, GRP78 (glucose-regulated protein 78 kDa). This unusual mechanism of regulating secretion from the constitutive secretory pathway provides a potentially missing link in the mechanism by which extracellular MANF protects cells from stresses that deplete SR/ER Calcium. Consistent with this was our finding that administration of recombinant MANF to mice decreased tissue damage in an in vivo model of myocardial infarction, a condition during which ER Calcium is known to be dysregulated, and MANF expression is induced.
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sarco endoplasmic reticulum Calcium atpase 2 expression is regulated by atf6 during the endoplasmic reticulum stress response intracellular signaling of Calcium stress in a cardiac myocyte model system
Journal of Biological Chemistry, 2001Co-Authors: Donna J Thuerauf, Holly Hoover, Julia Meller, Jessica Hernandez, Catherine Andrews, Wolfgang H Dillmann, Patrick M Mcdonough, Christopher C GlembotskiAbstract:The recently described transcription factor, ATF6, mediates the expression of proteins that compensate for potentially stressful changes in the endoplasmic reticulum (ER), such as reduced ER Calcium. In cardiac myocytes the maintenance of optimal Calcium levels in the sarcoplasmic reticulum (SR), a specialized form of the ER, is required for proper contractility. The present study investigated the hypothesis that ATF6 serves as a regulator of the expression of sarco/endoplasmic reticulum Calcium ATPase-2 (SERCA2), a protein that transports Calcium into the SR from the cytoplasm. Depletion of SR Calcium in cultured cardiac myocytes fostered the translocation of ATF6 from the ER to the nucleus, activated the promoter for rat SERCA2, and led to increased levels of SERCA2 protein. SERCA2 promoter induction by Calcium Depletion was partially blocked by dominant-negative ATF6, whereas constitutively activated ATF6 led to SERCA2 promoter activation. Mutation analyses identified a promoter-proximal ER stress-response element in the rat SERCA2 gene that was required for maximal induction by ATF6 and Calcium Depletion. Although this element was shown to be responsible for all of the effects of ATF6 on SERCA2 promoter activation, it was responsible for only a portion of the effects of Calcium Depletion. Thus, SERCA2 induction in response to Calcium Depletion appears to be a potentially physiologically important compensatory response to this stress that involves intracellular signaling pathways that are both dependent and independent of ATF6.
