Activation of Wnt Signaling by Chemically Induced Dimerization of LRP5 Disrupts Cellular Homeostasis
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{"title"=>"Activation of Wnt signaling by chemically induced dimerization of LRP5 disrupts cellular homeostasis", "type"=>"journal", "authors"=>[{"first_name"=>"Payam", "last_name"=>"Shahi", "scopus_author_id"=>"54882481100"}, {"first_name"=>"Dongsu", "last_name"=>"Park", "scopus_author_id"=>"8437663600"}, {"first_name"=>"Adam C.", "last_name"=>"Pond", "scopus_author_id"=>"36133742800"}, {"first_name"=>"Mamatha", "last_name"=>"Seethammagari", "scopus_author_id"=>"14032032200"}, {"first_name"=>"Shin Heng", "last_name"=>"Chiou", "scopus_author_id"=>"51161001100"}, {"first_name"=>"Kyucheol", "last_name"=>"Cho", "scopus_author_id"=>"56316380600"}, {"first_name"=>"Julienne L.", "last_name"=>"Carstens", "scopus_author_id"=>"54933719000"}, {"first_name"=>"William K.", "last_name"=>"Decker", "scopus_author_id"=>"34973936500"}, {"first_name"=>"Pierre D.", "last_name"=>"McCrea", "scopus_author_id"=>"7004042131"}, {"first_name"=>"Michael M.", "last_name"=>"Ittmann", "scopus_author_id"=>"7004507505"}, {"first_name"=>"Jeffrey M.", "last_name"=>"Rosen", "scopus_author_id"=>"57197820135"}, {"first_name"=>"David M.", "last_name"=>"Spencer", "scopus_author_id"=>"7401446161"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22303459", "sgr"=>"84856401425", "doi"=>"10.1371/journal.pone.0030814", "scopus"=>"2-s2.0-84856401425", "pui"=>"364167977", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"a59b6c9f-22a1-33b7-915e-44bdc3e9b129", "abstract"=>"Wnt signaling is crucial for a variety of biological processes, including body axis formation, planar polarity, stem cell maintenance and cellular differentiation. Therefore, targeted manipulation of Wnt signaling in vivo would be extremely useful. By applying chemical inducer of dimerization (CID) technology, we were able to modify the Wnt co-receptor, low-density lipoprotein (LDL)-receptor-related protein 5 (LRP5), to generate the synthetic ligand inducible Wnt switch, iLRP5. We show that iLRP5 oligomerization results in its localization to disheveled-containing punctate structures and sequestration of scaffold protein Axin, leading to robust β-catenin-mediated signaling. Moreover, we identify a novel LRP5 cytoplasmic domain critical for its intracellular localization and casein kinase 1-dependent β-catenin signaling. Finally, by utilizing iLRP5 as a Wnt signaling switch, we generated the Ubiquitous Activator of β-catenin (Ubi-Cat) transgenic mouse line. The Ubi-Cat line allows for nearly ubiquitous expression of iLRP5 under control of the H-2K(b) promoter. Activation of iLRP5 in isolated prostate basal epithelial stem cells resulted in expansion of p63(+) cells and development of hyperplasia in reconstituted murine prostate grafts. Independently, iLRP5 induction in adult prostate stroma enhanced prostate tissue regeneration. Moreover, induction of iLRP5 in male Ubi-Cat mice resulted in prostate tumor progression over several months from prostate hyperplasia to adenocarcinoma. We also investigated iLRP5 activation in Ubi-Cat-derived mammary cells, observing that prolonged activation results in mammary tumor formation. Thus, in two distinct experimental mouse models, activation of iLRP5 results in disruption of tissue homeostasis, demonstrating the utility of iLRP5 as a novel research tool for determining the outcome of Wnt activation in a precise spatially and temporally determined fashion.", "link"=>"http://www.mendeley.com/research/activation-wnt-signaling-chemically-induced-dimerization-lrp5-disrupts-cellular-homeostasis", "reader_count"=>30, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>2, "Student > Master"=>5, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>10, "Student > Postgraduate"=>2, "Student > Master"=>5, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>18, "Medicine and Dentistry"=>4, "Arts and Humanities"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>18}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Brazil"=>1, "Portugal"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/689258"], "description"=>"<p>Ubi-Cat mammary cells were isolated from 6–8 week adult female Ubi-Cat mice. 5×10<sup>3</sup> WT or Ubi-Cat mammary cells were transplanted into virgin adult recipients. WT and untreated Ubi-Cat cells demonstrated normal mammary outgrowth 8 weeks after transplant. Activation of iLRP via AP20187 resulted in formation of hyperplastic mammary ducts in 4 of 6 grafts. Two of six CID-treated grafts formed mammary tumors.</p>", "links"=>[], "tags"=>["gland", "transplant", "assay", "ubi-cat-derived", "mammary"], "article_id"=>359735, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g012", "stats"=>{"downloads"=>2, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Mammary_gland_transplant_assay_using_Ubi_Cat_derived_mammary_cells_/359735", "title"=>"Mammary gland transplant assay using Ubi-Cat-derived mammary cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:42:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/688191"], "description"=>"<p>(<b>A</b>) (left) Schematic of LRP5c deletion mutants (iLRP5 Δ1–5) comprised of synthetic ligand-binding domains (F<sub>v′</sub>-F<sub>vls</sub>). Numbers indicate N-terminal amino acid position of each deletion mutant. Red and black lines represent indicated sequences and gray lines represent PPPSP motifs, respectively <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030814#pone.0030814-Davidson1\" target=\"_blank\">[24]</a>. (right) Domain analysis of LRP5c on Wnt/β-catenin signaling. 293 cells were transiently transfected with 1 µg each of indicated constructs along with TCF-SEAP reporter. After 24 hours, cell aliquots were treated with indicated concentrations of AP20187, and SEAP activity was measured after an additional 24-hour incubation. Data represent two independent experiments with similar results. (<b>B</b>) Role of novel and CK1 sites in the interaction of Axin and iLRP5. 293 cells were transfected with 1 µg each of indicated mutants of iLRP5 along with an Axin expression construct. After 24-hour treatment with 100 nM AP20187 (+CID), Axin was immunoprecipitated from whole cell lysates with anti-myc antibody (α-myc). Co-immunoprecipitation of LRP5c was analyzed by anti-HA blot (α-HA). Amount of iLRP5 mutant expression was determined by HA blot (Input: α-HA). (<b>C</b>) Subcellular localization of iLRP5-truncation mutants. 293 cells were transfected with 1 µg of indicated plasmids. Twenty-four hours after transfection, 100 nM FK1012 was added for an additional 24 hours to induce dimerization. After fixation, cells were examined by fluorescence microscopy.</p>", "links"=>[], "tags"=>["sites", "lrp5c", "localization"], "article_id"=>358668, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Two_distinct_regulatory_sites_in_LRP5c_are_critical_for_function_and_localization_of_iLRP5_/358668", "title"=>"Two distinct regulatory sites in LRP5c are critical for function and localization of iLRP5.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:24:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/688602"], "description"=>"<p>(<b>A</b>) qRT-PCR analysis of Wnt target genes. LSCs were cultured in Matrigel for 6 days with or without CID (100 nM). Cells were isolated and RNA was collected for cDNA synthesis and qRT-PCR analysis. CID-mediated iLRP5 activation promotes Wnt target genes expression. Error bars represent StDev of 3 experiments, normalized to 18S RNA (<b>B</b>) Prolonged (16 days) activation of iLRP5 promotes enlargement of prostaspheres. Control spheres grew to maximum size of 150–200 µm; however, CID-treated spheres grew to 300–400 µm. Bar = 100 µm. (<b>C</b>) Analysis of p63 and β-catenin expression in prostasphere cross-sections. iLRP5 activation enhances β-catenin stability. CID-treated spheres reveal dispersed distribution of p63<sup>+</sup> cells within all layers of prostasphere. Bar = 100 µm.</p>", "links"=>[], "tags"=>["ilrp5", "activation", "prostate"], "article_id"=>359080, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g008", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vitro_analysis_of_iLRP5_activation_in_prostate_B_SCs_/359080", "title"=>"<i>In vitro</i> analysis of iLRP5 activation in prostate B/SCs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:31:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/688310"], "description"=>"<p>(<b>A</b>) Cross-species analysis of the novel LRP5 (<sub>1516</sub>MFYSSNIPATVRPYRPY<sub>1531</sub>) sequence. (<b>B</b>) Membrane targeting of the cytoplasmic moiety of LRP5 (M<sub>F</sub>-LRP5) and three variants containing mutations of possible phosphorylation sites: (1) YSS→FAA, (2) YRPY→FLPF and (3) YSS→FAA and YRPY→FLPF. The mutants have reduced Wnt pathway inducibility. Western blot indicates comparable protein expression from respective TCF-SEAP assay. (<b>C</b>) Comparison of iLRP5 and iLRP5 mutants. YSS→FAA and YRPY→FLPF mutants have lower TCF-SEAP activity. The double mutant fails to activate Wnt signaling. Western blot indicates protein expression from respective TCF-SEAP assay. (B and C), Data representative of two separate experiments performed in triplicates.</p>", "links"=>[], "tags"=>["lrp5", "wnt"], "article_id"=>358790, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g006", "stats"=>{"downloads"=>3, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_novel_region_of_LRP5_1516_MFYSSNIPATVRPYRPY_1531_is_required_for_Wnt_signaling_/358790", "title"=>"A novel region of LRP5 (<sub>1516</sub>MFYSSNIPATVRPYRPY<sub>1531</sub>) is required for Wnt signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:26:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/688041"], "description"=>"<p>(<b>A</b>) 293 cells were co-transfected with 1 µg TCF-reporter and iLRP5 construct and incubated for 24 hours with indicated concentrations (nM) of MAPK (PD98059 (PD)), PI3K (wortmannin (Wort)), Akt (Akt-i), or casein kinase 1 (CK1-i) inhibitor. (<b>B</b>) 293 cells were co-transfected with 1 µg NF-κB-reporter and hCD40 construct and incubated for 24 hours with indicated nM concentrations of CK1-i plus hCD40L (1 µg/mL). SEAP activity was measured after an additional 24-hour incubation with or without 100 nM CID (AP20187). Data is representative of at least two independent experiments. The amount of protein expression was normalized by anti-HA blot (α-HA).</p>", "links"=>[], "tags"=>["ilrp5-mediated"], "article_id"=>358519, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g004", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CK1_is_required_for_iLRP5_mediated_946_catenin_activation_/358519", "title"=>"CK1 is required for iLRP5-mediated β-catenin activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:21:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/687766"], "description"=>"<p>(<b>A</b>) Effects of dimerization and membrane translocation of LRP5c on Wnt/β-catenin signaling. Activation of the TCF reporter in 293 cells transiently transfected with 1 µg each TCF-SEAP reporter and M<sub>F</sub>-LRP5c (○), M<sub>F</sub>-FRB<sub>l</sub>2+F3-GFP (•), F3-LRP5c (□) or M<sub>F</sub>-FRB<sub>l</sub>2+F3-LRP5c (▪) expression plasmids is shown. After 24 hours, cell aliquots were treated with CID and suboptimal (5 nM) Rap-B, and SEAP activity was measured after 24 hours. (<b>B</b>) Effect of Axin on iLRP5-mediated β-catenin activation. 293 cells were transiently transfected with 1 µg each of TCF-SEAP and iLRP5 plasmids with our without myc-tagged Axin. After 24 hours, cells were treated with 100 nM CID (AP20187) or diluent alone, and SEAP activity was measured after an additional 24 hours. Protein expression levels were determined by anti-myc and anti-HA blotting (inset). (<b>C</b>) Dimerization-dependent interaction of Axin and iLRP5. 293 cells were transfected with 1 µg of indicated combinations of iLRP5 and Axin. After treatment with 100 nM homodimer (AP20187) for 24 hours (lane 2, 4), whole cell lysates were immunoprecipitated with anti-myc antibody (myc). Co-immunoprecipitation of LRP5c was analyzed by anti-HA blot (HA). Backbone (F<sub>v′</sub>-F<sub>vls</sub>-HA) or iLRP5 (F<sub>v′</sub>-F<sub>vls</sub>-iLRP5-HA) protein expression was detected by anti-HA blot (Input: HA). All data are representative of at least two (panel A) or three (panels B–C) independent experiments with similar results. Error bars (B) represent S.D. of triplicate measurements.</p>", "links"=>[], "tags"=>["downstream", "ilrp5", "interacts"], "article_id"=>358242, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Axin_is_a_critical_downstream_regulator_of_iLRP5_and_interacts_with_iLRP5_/358242", "title"=>"Axin is a critical downstream regulator of iLRP5 and interacts with iLRP5.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:17:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/687641"], "description"=>"<p>Schematics (top) and TCF reporter activity (bottom) of CID-mediated membrane translocation (<b>A</b>) with dimerization (<b>B</b>) of the LRP5 cytoplasmic domain (LRP5c). 293 cells were transiently transfected with TOP-SEAP reporter plasmid along with plasmids encoding myristoylated LRP5c (M<sub>F</sub>-LRP5c) or lipid raft-docking construct, M<sub>F</sub>-FRB<sub>l</sub>2, along with either LRP5c fused to 3 tandem rapalog-binding domains (F3-LRP5c) or control protein, F3-eGFP. TOP-SEAP activity was measured 24 hours after administration of indicated amounts of Rapalog-B (Rap-B) (<b>A</b>) or homodimer (FK1012) along with suboptimal levels of Rap-B (50 nM) (<b>B</b>). Protein expression levels are indicated by anti-HA western blot (inset).</p>", "links"=>[], "tags"=>["forms", "constitutive", "dimers", "cid-mediated", "dimerization", "lrp5", "induces"], "article_id"=>358113, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_LRP5_forms_constitutive_dimers_and_CID_mediated_dimerization_of_LRP5_induces_TCF_946_catenin_activity_/358113", "title"=>"LRP5 forms constitutive dimers and CID-mediated dimerization of LRP5 induces TCF/β-catenin activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:15:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/688719"], "description"=>"<p>(<b>A</b>) H&E analysis of prostate grafts. Activation of iLRP5 for 8 weeks resulted in formation of hyperplastic acini in prostate grafts. Bar = 100 µm. (<b>B</b>) Immunostaining of prostate grafts using cyclin D1 antibody. Bar = 50 µm (<b>C</b>) Immunostaining of prostate grafts using p63 antibody, Activation of iLRP5 resulted in over two-fold increase in the number of p63<sup>+</sup> cells. Data representative of 9 +CID and 9 −CID grafts. Bar = 50 µm.</p>", "links"=>[], "tags"=>["ilrp", "prostate", "hyperplasia", "reconstituted"], "article_id"=>359197, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g009", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_iLRP_promotes_prostate_hyperplasia_in_the_prostate_reconstituted_grafts_/359197", "title"=>"Activation of iLRP promotes prostate hyperplasia in the prostate reconstituted grafts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:33:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/688864"], "description"=>"<p>(<b>A</b>) Activation of iLRP5 increases size and weight of treated grafts. (<b>B</b>) Induction of iLRP5 in prostate stroma enhances prostate regeneration in treated grafts. Data representative of 6 +CID and 6 −CID grafts. Bar = 200 µm.</p>", "links"=>[], "tags"=>["prostate", "reconstitution", "comprising", "ubi-cat", "stroma", "wt"], "article_id"=>359342, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g010", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_prostate_reconstitution_comprising_adult_Ubi_Cat_prostate_stroma_and_WT_LSCs_/359342", "title"=>"Analysis of prostate reconstitution comprising adult Ubi-Cat prostate stroma and WT LSCs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:35:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/689042"], "description"=>"<p>Treatment of Ubi-Cat mice (n = 6) with AP20187 starting at 6 weeks of age for 52 weeks leads to development of prostate adenocarcinoma (2 of 6). Age-matched WT and untreated Ubi-Cat prostates (n = 6) appeared normal. Bar = 200 µm.</p>", "links"=>[], "tags"=>["cid-mediated", "ilrp5", "activation", "prostate"], "article_id"=>359516, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g011", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_CID_mediated_iLRP5_activation_in_the_intact_prostate_results_in_prostate_tumor_development_/359516", "title"=>"<i>In vivo</i> CID-mediated iLRP5 activation in the intact prostate results in prostate tumor development.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:38:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/350502", "https://ndownloader.figshare.com/files/350530", "https://ndownloader.figshare.com/files/350588", "https://ndownloader.figshare.com/files/350636", "https://ndownloader.figshare.com/files/350675", "https://ndownloader.figshare.com/files/350712"], "description"=>"<div><p>Wnt signaling is crucial for a variety of biological processes, including body axis formation, planar polarity, stem cell maintenance and cellular differentiation. Therefore, targeted manipulation of Wnt signaling <em>in vivo</em> would be extremely useful. By applying chemical inducer of dimerization (CID) technology, we were able to modify the Wnt co-receptor, low-density lipoprotein (LDL)-receptor-related protein 5 (LRP5), to generate the synthetic ligand inducible Wnt switch, iLRP5. We show that iLRP5 oligomerization results in its localization to disheveled-containing punctate structures and sequestration of scaffold protein Axin, leading to robust β-catenin-mediated signaling. Moreover, we identify a novel LRP5 cytoplasmic domain critical for its intracellular localization and casein kinase 1-dependent β-catenin signaling. Finally, by utilizing iLRP5 as a Wnt signaling switch, we generated the Ubiquitous Activator of β-catenin (Ubi-Cat) transgenic mouse line. The Ubi-Cat line allows for nearly ubiquitous expression of iLRP5 under control of the H-2K<sup>b</sup> promoter. Activation of iLRP5 in isolated prostate basal epithelial stem cells resulted in expansion of p63<sup>+</sup> cells and development of hyperplasia in reconstituted murine prostate grafts. Independently, iLRP5 induction in adult prostate stroma enhanced prostate tissue regeneration. Moreover, induction of iLRP5 in male Ubi-Cat mice resulted in prostate tumor progression over several months from prostate hyperplasia to adenocarcinoma. We also investigated iLRP5 activation in Ubi-Cat-derived mammary cells, observing that prolonged activation results in mammary tumor formation. Thus, in two distinct experimental mouse models, activation of iLRP5 results in disruption of tissue homeostasis, demonstrating the utility of iLRP5 as a novel research tool for determining the outcome of Wnt activation in a precise spatially and temporally determined fashion.</p> </div>", "links"=>[], "tags"=>["activation", "wnt", "signaling", "chemically", "induced", "dimerization", "lrp5", "disrupts", "cellular", "homeostasis"], "article_id"=>129271, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0030814.s001", "https://dx.doi.org/10.1371/journal.pone.0030814.s002", "https://dx.doi.org/10.1371/journal.pone.0030814.s003", "https://dx.doi.org/10.1371/journal.pone.0030814.s004", "https://dx.doi.org/10.1371/journal.pone.0030814.s005", "https://dx.doi.org/10.1371/journal.pone.0030814.s006"], "stats"=>{"downloads"=>3, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Activation_of_Wnt_Signaling_by_Chemically_Induced_Dimerization_of_LRP5_Disrupts_Cellular_Homeostasis/129271", "title"=>"Activation of Wnt Signaling by Chemically Induced Dimerization of LRP5 Disrupts Cellular Homeostasis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-01-27 02:34:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/687926"], "description"=>"<p>(<b>A, B</b>) Subcellular localization of dimerized LRP5c and disheveled. 293 cells were transfected with 1 µg each of plasmids expressing drug-binding domains fused with GFP (F3-GFP) or GFP-LRP5c (F3-GFP-LRP5c) with (B) or without (A) RFP-fused disheveled construct, Dvl-RFP. Twenty-four hours after transfection, 100 nM FK1012 was added for an additional 24 hours to induce F3-LRP5c dimerization. After fixation, cells were labeled with cholera toxin B (CTx-B-TRITC) (A) and examined by fluorescence microscopy. (<b>C, D</b>) Independent role of iLRP5 and disheveled in β-catenin activation. 293 cells were transfected with 1 µg TCF-SEAP reporter along with 0.5 µg of iLRP5 and the indicated amounts (µg) of Axin or dominant negative disheveled (Dix) constructs (C) or 0.5 µg disheveled construct (D). Twenty-four hours after transfection, 100 nM CID was added and SEAP activity was measured after 24 hours. Data is representative of at least three independent experiments (A, B). Error bars indicate mean ± S.D. of triplicate measurements (C. D).</p>", "links"=>[], "tags"=>["localizes", "disheveled-containing", "punctate"], "article_id"=>358406, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dimerized_iLRP5_localizes_to_disheveled_containing_punctate_structures_/358406", "title"=>"Dimerized-iLRP5 localizes to disheveled-containing punctate structures.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:20:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/688486"], "description"=>"<p>(<b>A</b>) 293 cells were co-transfected with Ubi-Cat expression plasmid (0.5 µg) along with TCF-SEAP reporter (0.2 µg). Cells were induced with AP20187 (100 nM) for 48 hours. Cell lysate and media were collected for examination of iLRP5 activity. Western blot analysis indicates iLRP5-dependent stabilization of cytoplasmic β-catenin, consistent with accompanying SEAP reporter assay. (<b>B</b>). Analysis of CBR expression via IVIS. (<b>C</b>) qRT-PCR analysis of iLRP5 expression in selected Ubi-Cat tissues using a transgene-specific primer-probe set.</p>", "links"=>[], "tags"=>["ilrp5", "ubi-cat", "transgenic"], "article_id"=>358962, "categories"=>["Molecular Biology", "Biotechnology"], "users"=>["Payam Shahi", "Dongsu Park", "Adam C. Pond", "Mamatha Seethammagari", "Shin-Heng Chiou", "Kyucheol Cho", "Julienne L. Carstens", "William K. Decker", "Pierre D. McCrea", "Michael M. Ittmann", "Jeffrey M. Rosen", "David M. Spencer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0030814.g007", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_iLRP5_expression_in_Ubi_Cat_transgenic_mice_/358962", "title"=>"Analysis of iLRP5 expression in Ubi-Cat transgenic mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-01-27 02:29:22"}

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Relative Metric

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