VEGFR2 Translocates to the Nucleus to Regulate Its Own Transcription
Publication Date
September 28, 2011
Journal
PLOS ONE
Authors
Inês Domingues, José Rino, Jeroen A. A. Demmers, Primal De Lanerolle, et al
Volume
6
Issue
9
Pages
e25668
DOI
https://dx.plos.org/10.1371/journal.pone.0025668
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0025668
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/21980525
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182252
Europe PMC
http://europepmc.org/abstract/MED/21980525
Web of Science
000295936900090
Scopus
80053242320
Mendeley
http://www.mendeley.com/research/vegfr2-translocates-nucleus-regulate-own-transcription
Events
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Mendeley | Further Information

{"title"=>"VEGFR2 translocates to the nucleus to regulate its own transcription", "type"=>"journal", "authors"=>[{"first_name"=>"Inês", "last_name"=>"Domingues", "scopus_author_id"=>"57057455900"}, {"first_name"=>"José", "last_name"=>"Rino", "scopus_author_id"=>"7003635454"}, {"first_name"=>"Jeroen A.A.", "last_name"=>"Demmers", "scopus_author_id"=>"6603445369"}, {"first_name"=>"Primal", "last_name"=>"de Lanerolle", "scopus_author_id"=>"7003507203"}, {"first_name"=>"Susana Constantino Rosa", "last_name"=>"Santos", "scopus_author_id"=>"7102756270"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-80053242320", "sgr"=>"80053242320", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0025668", "pmid"=>"21980525", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pui"=>"362648480"}, "id"=>"ffd7f7c9-d3b4-3737-9ca8-7c7d7400f832", "abstract"=>"Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is the major mediator of the angiogenic effects of VEGF. In addition to its well known role as a membrane receptor that activates multiple signaling pathways, VEGFR2 also has a nuclear localization. However, what VEGFR2 does in the nucleus is still unknown. In the present report we show that, in endothelial cells, nuclear VEGFR2 interacts with several nuclear proteins, including the Sp1, a transcription factor that has been implicated in the regulation of genes needed for angiogenesis. By in vivo chromatin immunoprecipitation (ChIP) assays, we found that VEGFR2 binds to the Sp1-responsive region of the VEGFR2 proximal promoter. These results were confirmed by EMSA assays, using the same region of the VEGFR2 promoter. Importantly, we show that the VEGFR2 DNA binding is directly linked to the transcriptional activation of the VEGFR2 promoter. By reporter assays, we found that the region between -300/-116 relative to the transcription start site is essential to confer VEGFR2-dependent transcriptional activity. It was previously described that nuclear translocation of the VEGFR2 is dependent on its activation by VEGF. In agreement, we observed that the binding of VEGFR2 to DNA requires VEGF activation, being blocked by Bevacizumab and Sunitinib, two anti-angiogenic agents that inhibit VEGFR2 activation. Our findings demonstrate a new mechanism by which VEGFR2 activates its own promoter that could be involved in amplifying the angiogenic response.", "link"=>"http://www.mendeley.com/research/vegfr2-translocates-nucleus-regulate-own-transcription", "reader_count"=>65, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>18, "Student > Postgraduate"=>7, "Student > Master"=>10, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>18, "Student > Postgraduate"=>7, "Student > Master"=>10, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>6, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>35, "Medicine and Dentistry"=>9, "Neuroscience"=>1, "Sports and Recreations"=>1, "Veterinary Science and Veterinary Medicine"=>1, "Physics and Astronomy"=>1, "Chemistry"=>2, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>6}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>35}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>2}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "Netherlands"=>1, "Belgium"=>1, "United States"=>5, "Brazil"=>1, "United Kingdom"=>1, "Portugal"=>1, "Switzerland"=>1, "Spain"=>1}, "group_count"=>1}

CrossRef

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/731045"], "description"=>"<p>(A) Cytoplasmic (C) and nuclear extracts (N) from EC IRES GFP and EC VEGFR2 IRES GFP were analysed by Immunoblot with antibodies against VEGFR2, Cyclin A, Sp1, p65, YY1. P-IkB and Lamin B were used as cytoplasmic and nuclear controls, respectively. (B) Nuclear extracts from EC IRES GFP (lanes 2,7) and EC VEGFR2 IRES GFP (lanes 3,8) were incubated with NFkB (left panel, lanes 2 and 3) or YY1 (right panel, lanes 7 and 8) radiolabeled probes. Four NFkB (C1–C4) or five YY1 complexes (C1–C5) are indicated with black arrows. Specific anti-p65 (lane 4) or anti-YY1 (lane 9) were introduced in the binding reaction to analyse the appearance of a supershift complex (as indicated in both panels) in EC VEGFR2 IRES GFP cells. Using the same cells, a competitive assay using 100x excess of cold probe of NFkB (lane 5) or YY1 (lane10) was performed. Control lanes 1 and 6 contain only the radiolabeled probes. (C) EC were cultured in growing media, treated or not with 6.12 Ab for 1 h and incubated with 5-FU for 15 min. (D) EC were cultured in growing media and transfected with scrambled siRNA or VEGFR2 siRNA. EC were incubated with 5-FU for 15 min. (C and D) 24 post-transfection. Cells were fixed and sequentially labeled on the same slide with a rabbit anti-human VEGFR2 (red fluorescence) and a mouse anti-human BrdU antibody (green fluorescence) and analysed by confocal microscopy. Results shown are representative z-projections of three independent experiments. Scale bar: 20 µm.</p>", "links"=>[], "tags"=>["internalization", "levels", "correlate", "transcriptional"], "article_id"=>401401, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025668.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VEGFR2_nuclear_internalization_levels_correlate_with_transcriptional_activity_of_EC_/401401", "title"=>"VEGFR2 nuclear internalization levels correlate with transcriptional activity of EC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-28 00:23:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/731282"], "description"=>"<p>(A) Sequence of the human <i>VEGFR2</i> proximal promoter (retrieved from Ensemble database accession number: ENSG00000128052) and outline of putative Sp1 binding sites. The transcription start site is indicated in gray. (B) ChIP assays of the <i>VEGFR2</i> proximal promoter were performed using EC cultured in growing media. Antibodies against VEGFR2 and Sp1 were used. Normal rabbit/mouse IgG were used as control. Also, an antibody for RNA Pol II was used to test the promoter activity. All values are relative to control IgG background and normalized to an intergenic region. Data are mean ± s.e.m. of triplicates and represents three independent experiments. (C) ChIP assays of the <i>VEGFR2</i> proximal promoter were performed in EC 24 h post-transfection of scrambled siRNA or VEGFR2 siRNA or Sp1 siRNA. Antibodies against VEGFR2 and Sp1 were used. Normal rabbit IgG was used as control. Values are relative to control IgG background and normalized to an intergenic region. Data are mean ± s.e.m. of triplicates and represents three independent experiments. (D) EMSA analysis of the <i>VEGFR2</i> promoter with EC nuclear extracts (lane 2) or VEGFR2 immunodepleted (ID VEGFR2) extract (lane 3) were conducted. Four complexes (C1-C4) are indicated with black arrows. A competitive assay using 100x excess of cold probe of VEGFR2 promoter was conducted (lane 4) using EC nuclear extract. Control lane 1 contains only the radiolabeled probe.</p>", "links"=>[], "tags"=>["vegfr2", "binds", "proximal", "promoter"], "article_id"=>401633, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025668.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nuclear_VEGFR2_binds_to_the_VEGFR2_proximal_promoter_in_EC_/401633", "title"=>"Nuclear VEGFR2 binds to the <i>VEGFR2</i> proximal promoter in EC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-28 00:27:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/730869"], "description"=>"<p>(A) EC, EC IRES GFP and EC VEGFR2 IRES GFP were cultured in growing media and VEGFR2 overexpression was analysed by immunofluorescence. Cells were stained with a rabbit anti-human VEGFR2 antibody (Alexa 594). Results shown are representative z-projections of at least three independent experiments. Scale bar: 20 µm. Right panel shows mean fluorescence intensity of VEGFR2 in the cell nucleus. *<i>p</i><0.0001. (B and C) FRAP analysis was performed in EC VEGFR2-GFP and mutants EC VEGFR2(Y1054F/Y1059F)-GFP, EC VEGFR2(Y996F)-GFP and EC VEGFR2(Y951F)-GFP. Fluorescence signal of the entire nucleus was photobleached with a single 488-nm high intensity laser pulse and subsequent fluorescence recovery was recorded for 280 s. (B) Selected images of VEGFR2-GFP protein in EC VEGFR2-GFP (upper panel) and EC VEGFR2(Y951F)-GFP (lower panel) before bleaching (steady-state) at the indicated intervals post-bleaching (from 5 to 100 s). White circles indicate the bleached region. (C) Fluorescence intensity in the bleached region was measured every 5 s for 280 s and normalized for the initial intensity. Data show results obtained in three independent experiments, with at least ten different cells analysed in each case. Error bars represent standard deviation (SD).</p>", "links"=>[], "tags"=>["translocation", "affected", "vegfr2", "tyrosine"], "article_id"=>401218, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025668.g001", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VEGFR2_nuclear_translocation_is_a_rapid_process_that_is_affected_by_the_VEGFR2_tyrosine_951_/401218", "title"=>"VEGFR2 nuclear translocation is a rapid process that is affected by the VEGFR2 tyrosine 951.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-28 00:20:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/731442"], "description"=>"<p>ChIP assays of the <i>VEGFR2</i> proximal promoter were performed using (A) EC cultured in basal medium for 48 h, and stimulated or not with VEGF (20 ng/ml) for 30 min. Antibodies against VEGFR2 and Sp1 were used. Normal rabbit/mouse IgG were used as control. Also, an antibody for RNA Pol II was used to test the promoter activity. Values are relative to control IgG background and normalized to an intergenic region. Data are mean ± s.e.m. of triplicates and represents three independent experiments. (B) EC cultured in growing media were treated or not with 0.5 mg/ml Bevacizumab (left panel) or 0.1 µM Sunitinib (right panel) for 16 h. In the Sunitinib experiments, DMSO was used as vehicle. ChIP values are relative to control IgG and normalized to an intergenic region. Data are mean ± s.e.m. of triplicates and represents three independent experiments.</p>", "links"=>[], "tags"=>["binding", "promoter", "vegfr2"], "article_id"=>401795, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025668.g006", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VEGFR2_binding_to_its_own_promoter_is_dependent_of_VEGFR2_activation_/401795", "title"=>"VEGFR2 binding to its own promoter is dependent of VEGFR2 activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-28 00:29:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/731361"], "description"=>"<p>(A) NIH 3T3 GFP and NIH 3T3 VEGFR2-GFP were transfected with pGL3 control or pGL3 VEGFR2 (-300/+1) or pGL3 VEGFR2 (-116/+1). The β-gal plasmid was co-transfected as a control. Promoter activities were measured with luciferase activity normalized to β-gal. The results are expressed as the relative luciferase activities. Data are mean ± s.e.m. of relative luciferase activities from four independent experiments, each performed in triplicate. *<i>p</i> = 0.007; **<i>p</i> = 0.001). (B) NIH 3T3 VEGFR2-GFP were transfected with scrambled siRNA, VEGFR2 siRNA or Sp1 siRNA. At 48 h post-transfection the relative luciferase activity of pGL3 control or pGL3 VEGFR2 (-300/+1) was measured. Data are mean ± s.e.m. of relative luciferase activities from three independent experiments, each performed in triplicate, (*<i>p</i>  = 0.003).</p>", "links"=>[], "tags"=>["vegfr2", "activates", "proximal"], "article_id"=>401713, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025668.g005", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nuclear_VEGFR2_activates_the_human_VEGFR2_proximal_promoter_/401713", "title"=>"Nuclear VEGFR2 activates the human <i>VEGFR2</i> proximal promoter.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-28 00:28:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/368884", "https://ndownloader.figshare.com/files/368928", "https://ndownloader.figshare.com/files/368964", "https://ndownloader.figshare.com/files/368997"], "description"=>"<div><p>Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is the major mediator of the angiogenic effects of VEGF. In addition to its well known role as a membrane receptor that activates multiple signaling pathways, VEGFR2 also has a nuclear localization. However, what VEGFR2 does in the nucleus is still unknown. In the present report we show that, in endothelial cells, nuclear VEGFR2 interacts with several nuclear proteins, including the Sp1, a transcription factor that has been implicated in the regulation of genes needed for angiogenesis. By <em>in vivo</em> chromatin immunoprecipitation (ChIP) assays, we found that VEGFR2 binds to the Sp1-responsive region of the <em>VEGFR2</em> proximal promoter. These results were confirmed by EMSA assays, using the same region of the <em>VEGFR2</em> promoter. Importantly, we show that the VEGFR2 DNA binding is directly linked to the transcriptional activation of the <em>VEGFR2</em> promoter. By reporter assays, we found that the region between -300/-116 relative to the transcription start site is essential to confer VEGFR2-dependent transcriptional activity. It was previously described that nuclear translocation of the VEGFR2 is dependent on its activation by VEGF. In agreement, we observed that the binding of VEGFR2 to DNA requires VEGF activation, being blocked by Bevacizumab and Sunitinib, two anti-angiogenic agents that inhibit VEGFR2 activation. Our findings demonstrate a new mechanism by which VEGFR2 activates its own promoter that could be involved in amplifying the angiogenic response.</p> </div>", "links"=>[], "tags"=>["vegfr2", "translocates", "nucleus", "transcription"], "article_id"=>132905, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0025668.s001", "https://dx.doi.org/10.1371/journal.pone.0025668.s002", "https://dx.doi.org/10.1371/journal.pone.0025668.s003", "https://dx.doi.org/10.1371/journal.pone.0025668.s004"], "stats"=>{"downloads"=>4, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/VEGFR2_Translocates_to_the_Nucleus_to_Regulate_Its_Own_Transcription/132905", "title"=>"VEGFR2 Translocates to the Nucleus to Regulate Its Own Transcription", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-09-28 00:48:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/731165"], "description"=>"<p>(A) Immunoprecipitation (IP) of 1 mg EC nuclear extract with anti-human VEGFR2 was performed and resolved in 8% SDS-PAGE, following silver staining (lane 2). VEGFR2 antibody plus beads (without N) were used as negative control for immunoprecipitation (lane 1). The protein marker is shown as molecular weight (MW) in thousands. (B) Representation of the mass spectrometry analysis of the nuclear VEGFR2 IP, showing the categories for the different biological functions of the identified proteins (p<0.05). (C) Immunoprecipitation (IP) of EC nuclear extracts (N) was conducted with the VEGFR2 (lane 2), Sp1 (lane 4) and rabbit IgG (rIgG-lane 5) antibodies followed by VEGFR2 (upper panel) or Sp1 (lower panel) immunoblotting. VEGFR2 (lane 1) or Sp1 (lane 3) antibodies plus beads (without N) were used as negative controls for immunoprecipitation. Non-immunoprecipitated nuclear cell extract (lane 6) was also included in the experiment. (D) Pull-down assay: Sp1 protein fused to a HA tag was incubated with GST alone (lanes 1 and 2) or VEGFR2 (789-1356)-GST (lanes 3 and 4). GST-unbound (UB) (lanes 1 and 3) and bound (B) fractions (lanes 2 and 4) were loaded and analyzed with GST (upper panel) and Sp1 (lower panel) antibodies.</p>", "links"=>[], "tags"=>["vegfr2", "interacts", "transcription", "sp1", "nucleus"], "article_id"=>401517, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology"], "users"=>["Inês Domingues", "José Rino", "Jeroen A. A. Demmers", "Primal de Lanerolle", "Susana Constantino Rosa Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025668.g003", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nuclear_VEGFR2_interacts_with_the_transcription_factor_Sp1_in_the_nucleus_of_EC_/401517", "title"=>"Nuclear VEGFR2 interacts with the transcription factor Sp1 in the nucleus of EC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-09-28 00:25:17"}

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