BOR-Syndrome-Associated Eya1 Mutations Lead to Enhanced Proteasomal Degradation of Eya1 Protein
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{"title"=>"BOR-syndrome-associated Eya1 mutations lead to enhanced proteasomal degradation of Eya1 protein", "type"=>"journal", "authors"=>[{"first_name"=>"Amna", "last_name"=>"Musharraf", "scopus_author_id"=>"6505563119"}, {"first_name"=>"Dagmar", "last_name"=>"Kruspe", "scopus_author_id"=>"18437008400"}, {"first_name"=>"Jürgen", "last_name"=>"Tomascha", "scopus_author_id"=>"56157512200"}, {"first_name"=>"Birgit", "last_name"=>"Besenbeck", "scopus_author_id"=>"6507302690"}, {"first_name"=>"Christoph", "last_name"=>"Englert", "scopus_author_id"=>"7005800792"}, {"first_name"=>"Kathrin", "last_name"=>"Landgraf", "scopus_author_id"=>"25621270800"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84900392606", "pmid"=>"24489909", "sgr"=>"84900392606", "doi"=>"10.1371/journal.pone.0087407", "isbn"=>"1932-6203", "issn"=>"19326203", "pui"=>"373070240"}, "id"=>"0ca4e15d-4c08-3089-8a29-b2b308ad202d", "abstract"=>"Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.", "link"=>"http://www.mendeley.com/research/borsyndromeassociated-eya1-mutations-lead-enhanced-proteasomal-degradation-eya1-protein", "reader_count"=>14, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>6, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1365364"], "description"=>"<p>(A) Eya domain of human Eya1 depicting the disease associated missense mutations included in this study. BOR branchio-oto-renal; BO branchio-otic; OD ocular defects. (B) Cellular localization of Eya1 and disease-associated Eya1 mutants. COS-7 cells were transfected with expression plasmids encoding EGFP-Eya1 or mutants either alone or in combination with Six2. Insets show counterstaining with Hoechst dye. (C) COS-7 cells were transfected with HA-tagged <i>Eya1</i> or mutants together with FLAG-Six2 or empty vector. Nuclear (N) and cytoplasmic (C) extracts were analyzed by immunoblotting.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Protein chemistry", "Protein interactions", "developmental biology", "Molecular development", "genetics", "Molecular genetics", "Gene regulation", "Genetic mutation", "Genetics of disease", "Molecular cell biology", "Membranes and sorting", "bor", "mutant", "l550p", "fails", "translocate", "nucleus"], "article_id"=>917201, "categories"=>["Biological Sciences"], "users"=>["Amna Musharraf", "Dagmar Kruspe", "Jürgen Tomasch", "Birgit Besenbeck", "Christoph Englert", "Kathrin Landgraf"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087407.g001", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_BOR_mutant_L550P_fails_to_translocate_into_the_nucleus_in_presence_of_Six_/917201", "title"=>"The BOR mutant L550P fails to translocate into the nucleus in presence of Six.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 02:43:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1365374"], "description"=>"<p>COS-7 cells were transfected with HA-Eya1 or mutants and FLAG-Six2 as indicated (left). In case of the mutant L550P cells were treated with MG132 (10 µM) to enhance protein levels (right). Six2 was immunoprecipitated using anti-FLAG antibody, and interacting Eya1 was detected by immunoblotting.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Protein chemistry", "Protein interactions", "developmental biology", "Molecular development", "genetics", "Molecular genetics", "Gene regulation", "Genetic mutation", "Genetics of disease", "Molecular cell biology", "Membranes and sorting", "stabilization", "requires"], "article_id"=>917210, "categories"=>["Biological Sciences"], "users"=>["Amna Musharraf", "Dagmar Kruspe", "Jürgen Tomasch", "Birgit Besenbeck", "Christoph Englert", "Kathrin Landgraf"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087407.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Eya1_stabilization_requires_interaction_with_Six_proteins_/917210", "title"=>"Eya1 stabilization requires interaction with Six proteins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 02:43:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1365367"], "description"=>"<p>(A) COS-7 cells were transfected with empty vector (control), HA-Eya1 or mutants, and FLAG-Six2. Equal amounts of protein were analyzed by SDS-PAGE and immunoblotting using anti-HA and anti-FLAG antibody. (B) Endogenous Eya1 is stabilized in presence of Six2. MK4 cells were transfected with <i>Eya1</i>-specific or non-target control siRNA and Eya1 protein levels were detected by immunoblotting using anti-Eya1 antibody (left). MK4 cells stably expressing FLAG-Six2 were subject to immunoblot analyses using Eya1-specific antibody (right). Asterisk indicates unspecific signal. (C) Six induces accumulation of Eya1 protein in different cell lines via the conserved Six and homeo domain. COS-7 and U2OS cells were transfected with HA-<i>Eya1</i> and expression vectors for <i>Six1</i>, <i>Six2</i>, C-terminal domain of Six2 (CD), <i>GDNF</i> and <i>H-Ras</i>. Eya1 protein levels were detected by immunoblotting using anti-HA antibody. (D) Schematic representation of the Six2 deletion constructs used for characterization of Eya1 stabilization (left). COS-7 cells were co-transfected with HA-Eya1, Six2 or deletion constructs as indicated. Eya1 protein levels were analyzed by immunoblotting.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Protein chemistry", "Protein interactions", "developmental biology", "Molecular development", "genetics", "Molecular genetics", "Gene regulation", "Genetic mutation", "Genetics of disease", "Molecular cell biology", "Membranes and sorting", "stabilize", "eya1", "mutants"], "article_id"=>917203, "categories"=>["Biological Sciences"], "users"=>["Amna Musharraf", "Dagmar Kruspe", "Jürgen Tomasch", "Birgit Besenbeck", "Christoph Englert", "Kathrin Landgraf"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087407.g002", "stats"=>{"downloads"=>6, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Six_proteins_stabilize_Eya1_and_Eya1_mutants_with_the_exception_of_L550P_/917203", "title"=>"Six proteins stabilize Eya1 and Eya1 mutants with the exception of L550P.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 02:43:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1365382", "https://ndownloader.figshare.com/files/1365383"], "description"=>"<div><p>Mutations in the human <i>EYA1</i> gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of <i>Eya1</i>-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The <i>Eya1</i> gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing <i>Eya1</i> missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated <i>Eya1</i> missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.</p></div>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Protein chemistry", "Protein interactions", "developmental biology", "Molecular development", "genetics", "Molecular genetics", "Gene regulation", "Genetic mutation", "Genetics of disease", "Molecular cell biology", "Membranes and sorting", "bor-syndrome-associated", "mutations", "enhanced", "proteasomal", "degradation", "eya1"], "article_id"=>917218, "categories"=>["Biological Sciences"], "users"=>["Amna Musharraf", "Dagmar Kruspe", "Jürgen Tomasch", "Birgit Besenbeck", "Christoph Englert", "Kathrin Landgraf"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0087407.s001", "https://dx.doi.org/10.1371/journal.pone.0087407.s002"], "stats"=>{"downloads"=>5, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/BOR_Syndrome_Associated_Eya1_Mutations_Lead_to_Enhanced_Proteasomal_Degradation_of_Eya1_Protein/917218", "title"=>"BOR-Syndrome-Associated <i>Eya1</i> Mutations Lead to Enhanced Proteasomal Degradation of Eya1 Protein", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-01-29 02:43:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/1365370"], "description"=>"<p>(A) Eya1 and its mutants accumulate in the presence of the proteasome inhibitor lactacystin. COS-7 cells were transfected with wild type or mutant HA-Eya1 or empty vector. 24 h post-transfection cells were treated with lactacystin (1 µM). Cells were lysed and Eya1 was detected by immunoblotting. (B) Eya1 is ubiquitinated. COS-7 cells were co-transfected with HA-Eya1 and HA-ubiquitin or His-ubiquitin. 24 h later, cells were treated with MG132 (10 µM) or DMSO for 24 h. For <i>in vivo</i> ubiquitination assay, His-ubiquitin-labelled proteins were purified from cell lysates followed by immunoblotting and detection of Eya1 using anti-Eya1 antibody. Asterisks indicate unspecific signals. (C) Schematic representation of the Eya1 mutants used for <i>in vivo</i> ubiquitination assay. Position of lysine residues is indicated in the scheme of full-length Eya1. (D) Eya1 ubiquitination occurs in two distinct regions of the Eya domain. COS-7 cells were co-transfected with His-ubiquitin and the indicated <i>Eya1</i> expression constructs, treated with MG132 (10 µM), and subjected to <i>in vivo</i> ubiquitination assay followed by immunoblotting and detection of Eya1 using anti-HA antibody. (E) Six proteins inhibit ubiquitination of Eya1. COS-7 cells overexpressing wild type or mutant HA-Eya1, His-ubiquitin and Six2 or empty vector were subjected to <i>in vivo</i> ubiquitination assay. Ubiquitinated Eya1 protein was detected by immunoblotting using anti-HA antibody. β-actin was used as a loading control for total cell lysate.</p>", "links"=>[], "tags"=>["Biochemistry", "proteins", "Protein chemistry", "Protein interactions", "developmental biology", "Molecular development", "genetics", "Molecular genetics", "Gene regulation", "Genetic mutation", "Genetics of disease", "Molecular cell biology", "Membranes and sorting", "degradation", "occurs", "proteasome", "inhibited"], "article_id"=>917206, "categories"=>["Biological Sciences"], "users"=>["Amna Musharraf", "Dagmar Kruspe", "Jürgen Tomasch", "Birgit Besenbeck", "Christoph Englert", "Kathrin Landgraf"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087407.g003", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Eya1_degradation_occurs_via_the_proteasome_and_is_inhibited_by_Six_proteins_/917206", "title"=>"Eya1 degradation occurs via the proteasome and is inhibited by Six proteins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 02:43:35"}

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  • {"unique-ip"=>"5", "full-text"=>"6", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"6", "full-text"=>"10", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"14", "full-text"=>"16", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"18", "full-text"=>"13", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}

Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[282]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[306, 482]}]}
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