Radiation-Induced c-Jun Activation Depends on MEK1-ERK1/2 Signaling Pathway in Microglial Cells
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{"title"=>"Radiation-induced c-Jun activation depends on MEK1-ERK1/2 signaling pathway in microglial cells", "type"=>"journal", "authors"=>[{"first_name"=>"Zhiyong", "last_name"=>"Deng", "scopus_author_id"=>"22936777500"}, {"first_name"=>"Guangchao", "last_name"=>"Sui", "scopus_author_id"=>"7006121787"}, {"first_name"=>"Paulo Mottin", "last_name"=>"Rosa", "scopus_author_id"=>"57198179478"}, {"first_name"=>"Weiling", "last_name"=>"Zhao", "scopus_author_id"=>"55303603800"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84860992169", "pmid"=>"22606284", "sgr"=>"84860992169", "doi"=>"10.1371/journal.pone.0036739", "isbn"=>"1932-6203", "issn"=>"19326203", "pui"=>"364803161"}, "id"=>"50cbbede-6046-314e-a872-3383e2ad66b1", "abstract"=>"Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation.", "link"=>"http://www.mendeley.com/research/radiationinduced-cjun-activation-depends-mek1erk12-signaling-pathway-microglial-cells", "reader_count"=>29, "reader_count_by_academic_status"=>{"Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>4, "Unspecified"=>2}, "reader_count_by_user_role"=>{"Researcher"=>9, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>4, "Unspecified"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>18, "Medicine and Dentistry"=>3, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>18}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"France"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/639596"], "description"=>"<p>BV2 cells were individually treated with U0126 (10 μM) and the JNK inhibitor SP600125 (5 μM). Cells were irradiated (10 Gy) or sham-irradiated. Cell lysates were collected 1 h post-irradiation. (A) Levels of p-c-Jun and p-ERK1/2 in the treated cells. (B) Levels of c-Jun, ERK, p-JNKs, and JNKs in the treated cells.</p>", "links"=>[], "tags"=>["c-jun", "phosphorylation", "bv2"], "article_id"=>310084, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g005", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_JNK_function_on_c_Jun_phosphorylation_in_BV2_cells_/310084", "title"=>"JNK function on c-Jun phosphorylation in BV2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 00:01:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/639496"], "description"=>"<p>(A) Cell lysates collected from 10 Gy-irradiated BV2 cells were immunoblotted with anti-phosphorylated MEK1/2 (sc-7995R) antibody. (B) BV2 cells were transfected with HA-MEK1, HA-MEK1<sup>K97M</sup> (kinase-dead mutant), and vector control. Protein levels of p-c-Jun and p-ERK1/2 (upper and lower panels) are shown. (C) BV2 cells that were treated or untreated with 10 μM U0126 were irradiated with 10 Gy. p-c-Jun and p-ERK1/2 levels were analyzed by Western blot. (D) Two shRNAs (sh-MEK1-212 and sh-MEK1-495) were lentivirally delivered into BV2 cells to knockdown MEK1 protein. Knockdown efficiency and protein levels of p-c-Jun and p-ERK1/2 were detected with the indicated antibodies. The quantification results for (C) and (D) are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036739#pone.0036739.s002\" target=\"_blank\">Figure S2</a>.</p>", "links"=>[], "tags"=>["signaling", "pathway", "radiation-induced", "c-jun"], "article_id"=>309987, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MEK_ERK1_2_signaling_pathway_is_required_for_radiation_induced_c_Jun_phosphorylation_/309987", "title"=>"MEK-ERK1/2 signaling pathway is required for radiation-induced c-Jun phosphorylation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 02:46:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/639156"], "description"=>"<p>(A) BV2 cells were irradiated with a single dose of 10 Gy, and sampled at the time points indicated. Cell lysates were sequentially immunoblotted with indicated antibodies in Western blot assays to detect phosphorylated and total proteins of c-Jun, ERK1/2, and JNK. β-actin was used as a loading control. Increased phosphorylation was found for c-Jun and ERK1/2 post irradiation, but not for JNKs. There was no obvious change for total c-Jun. The right panel shows the fold change for phosphorylation of c-Jun (Ser63 and Ser73) and ERK1/2 following irradiation. Data represent mean ± SD and the significant differences compared to control were indicated as *<i>p</i><0.05 or **<i>p</i><0.01. (B) BV2 cells were irradiated with different doses as shown and phosphorylation of c-Jun and ERK1/2 was detected at 0.5 and 1 h post-irradiation. Regardless of dose levels, radiation markedly stimulated phosphorylation of c-Jun and ERK1/2.</p>", "links"=>[], "tags"=>["phosphorylation", "c-jun", "bv2"], "article_id"=>309647, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Radiation_induced_phosphorylation_of_c_Jun_and_ERK1_2_in_BV2_cells_/309647", "title"=>"Radiation-induced phosphorylation of c-Jun and ERK1/2 in BV2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 02:40:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/330404", "https://ndownloader.figshare.com/files/330447", "https://ndownloader.figshare.com/files/330501", "https://ndownloader.figshare.com/files/330555", "https://ndownloader.figshare.com/files/330617", "https://ndownloader.figshare.com/files/330671"], "description"=>"<div><p>Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation.</p> </div>", "links"=>[], "tags"=>["radiation-induced", "c-jun", "activation", "depends", "signaling", "pathway", "microglial", "cells"], "article_id"=>125245, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0036739.s001", "https://dx.doi.org/10.1371/journal.pone.0036739.s002", "https://dx.doi.org/10.1371/journal.pone.0036739.s003", "https://dx.doi.org/10.1371/journal.pone.0036739.s004", "https://dx.doi.org/10.1371/journal.pone.0036739.s005", "https://dx.doi.org/10.1371/journal.pone.0036739.s006"], "stats"=>{"downloads"=>45, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Radiation_Induced_c_Jun_Activation_Depends_on_MEK1_ERK1_2_Signaling_Pathway_in_Microglial_Cells/125245", "title"=>"Radiation-Induced c-Jun Activation Depends on MEK1-ERK1/2 Signaling Pathway in Microglial Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-14 01:27:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/639394"], "description"=>"<p>(A) Direct protein interaction between c-Jun and ERK1/2. In GST pull-down binding assays, purified 6xHis-c-Jun protein (1.0 µg) was individually incubated with GST-ERK1 and GST-ERK2 containing beads (3 µg each). After extensive washing, an antibody (sc-45) against c-Jun was used to detect the 6xHis-c-Jun protein brought down from the glutathione agarose beads. Lower panel: Ponceau S-stained membrane transferred with the GST fusion proteins. (B–D) <i>In vitro</i> protein binding studies to determine the binding domains of ERK1/2 on c-Jun. (B). Schematic diagram of GST-fusion proteins created for wild-type c-Jun and truncated c-Jun including aa191-334 (DNA binding domain), aa1-190 (JBD and transactivation domains), and aa1-62 (JBD domain). (C) and (D) Binding assays for GST-c-Jun mutants with 6xHis-ERK1 and 6xHis-ERK2. (E) Interaction of endogenous c-Jun and phosphorylated ERK kinases in BV2 cells. BV2 cells were serum starved for 24 h and then irradiated or sham-irradiated with a single dose of 10 Gy. Cell lysates were collected 1 h after irradiation. 0.75 mg cell lysates were used in co-immunoprecipitation with the c-Jun antibody (sc-45). The phosphorylated and total ERK1/2 were detected with the antibody sc-81492 and sc-94, respectively.</p>", "links"=>[], "tags"=>["erk2", "c-jun", "vitro"], "article_id"=>309884, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ERK1_and_ERK2_interact_with_c_Jun_in_vitro_and_in_cells_/309884", "title"=>"ERK1 and ERK2 interact with c-Jun in vitro and in cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 02:44:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/639670"], "description"=>"<p>(A) 100 μM exogenous hydrogen peroxide was added into culture medium of BV2 cells. p-c-Jun and p-ERK1/2 were detected at the time points indicated. (B) c-Jun phosphorylation was detected for BV2 cell lysates treated or untreated with 5 mM NAC at the indicated time points after radiation. (C) Inhibition of radiation-induced ROS in BV2 cells by 50 μM apocynin. Intracellular ROS level was determined using the 2′, 7′-Dichlorofluorescein diacetate (DCFA-DA) based method. Data represent mean ± SD, *<i>p</i><0.05. (D) Apocynin was added into the BV2 cell culture medium and phosphorylation of c-Jun was analyzed in the apocynin-treated cell lysates.</p>", "links"=>[], "tags"=>["c-jun"], "article_id"=>310166, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ROS_is_associated_with_c_Jun_phosphorylation_/310166", "title"=>"ROS is associated with c-Jun phosphorylation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 00:02:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/639277"], "description"=>"<p>(A) BV2 cells were transiently cotransfected with ERK1 and ERK2 expression vectors in doses of 75, 150 and 300 ng for each plasmid. The total DNA amounts in transfection were compensated with an empty vector. The transfected ERK1 and ERK2 led to a dose-dependent increase of phosphorylated ERK1/2 and c-Jun. (B) BV2 cells were treated with 10 µM ERK kinase inhibitor (Calbiochem Cat #328006) and DMSO as a control. Inhibitor-treated or untreated cells were collected at 1 h after 10 Gy irradiation. Western blots showed that ERK kinase inhibitor abolished radiation-stimulated phosphorylation of ERK1/2 and c-Jun. (C) To detect knockdown effects for ERK1 and ERK2 by lentiviral shRNA constructs in BV2 cells, two lentivirual shRNAs were prepared for each ERK kinase, respectively, and used for infecting BV2 cells. The cells were collected 48 h after lentiviral infection and subjected for Western blot analysis using the antibody against ERK1 (K32, sc-94), which also can recognize ERK2. Efficient depletion was found in the cell lysates infected with sh-ERK1-974, sh-ERK2-321, and sh-ERK2-772, but not sh-ERK1-536. (D) BV2 cells were individually infected with scrambled control, ERK1, and ERK2 shRNA lentiviruses, and subsequently irradiated with 10 Gy 48 h post infection and sampled at 1 h following radiation. There was no effect on radiation-induced c-Jun phosphorylation by individual depletion of ERK kinases. (E) BV2 cells were infected with combined lentiviruses (sh-ERK1-974/sh-ERK2-321 and sh-ERK1-974/sh-ERK2-772) and irradiated (10 Gy). Both shRNA combinations reduced radiation-stimulated phosphorylation of ERK1 and ERK2 to low levels, and decreased phosphorylated c-Jun after radiation. Bar graph depicts quantification (means ± SD) of relative c-Jun phosphorylation level, **<i>p</i><0.01(#3 vs. #2; #4 vs. #2). (F) JNK levels in ERK1/2 knockdown BV2 cells.</p>", "links"=>[], "tags"=>["erk2", "indispensable", "radiation-induced", "c-jun", "phosphorylation", "bv2"], "article_id"=>309764, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ERK1_and_ERK2_are_indispensable_for_radiation_induced_c_Jun_phosphorylation_in_BV2_cells_/309764", "title"=>"ERK1 and ERK2 are indispensable for radiation-induced c-Jun phosphorylation in BV2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 02:42:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/639780"], "description"=>"<p>(A) Radiation-increased AP-1 DNA binding ability was reduced by MEK kinase inhibitor U0126. To determine the effect of U0126 on c-Jun DNA binding ability, different nuclear extracts as indicated were incubated with the γ-<sup>32</sup>p-labeled AP-1 consensus DNA probe. 5% acrylamide gel (0.5× TBE) was used to resolve the products of the binding reaction. Binding specificity is shown by the reaction only with BSA and competition with 50-fold excess non-radioactive consensus AP-1 oligonucleotide (cold AP-1 oligo). (B) BV2 cells were irradiated with 10 Gy dose with or without U0126. Cells were collected at the indicated time points and subsequently used to detect the expression of c-Jun target genes. Protein levels of COX-2 and cyclin D1 were examined by Western blot and transcription levels of TNFα, IL-1β, and IL-6 were examined by RT-PCR. (C) Real-time PCR was used to quantitatively analyze the expression of TNFα, IL-1β, and IL-6. Data represent mean ± SD, *<i>p</i><0.05; **<i>p</i><0.01.</p>", "links"=>[], "tags"=>["phosphorylation", "c-jun", "modulates", "transcriptional"], "article_id"=>310271, "categories"=>["Molecular Biology", "Biochemistry", "Neuroscience", "Cell Biology"], "users"=>["Zhiyong Deng", "Guangchao Sui", "Paulo Mottin Rosa", "Weiling Zhao"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036739.g007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Radiation_induced_phosphorylation_of_c_Jun_modulates_its_transcriptional_activity_/310271", "title"=>"Radiation-induced phosphorylation of c-Jun modulates its transcriptional activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-14 00:04:31"}

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Relative Metric

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