COMMD1 Promotes pVHL and O2-Independent Proteolysis of HIF-1α via HSP90/70
Publication Date
October 05, 2009
Journal
PLOS ONE
Authors
Bart Van De Sluis, Arjan J. Groot, Jeroen Vermeulen, Elsken Van Der Wall, et al
Volume
4
Issue
10
Pages
e7332
DOI
https://dx.plos.org/10.1371/journal.pone.0007332
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0007332
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/19802386
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750754
Europe PMC
http://europepmc.org/abstract/MED/19802386
Web of Science
000270593600010
Scopus
70350012306
Mendeley
http://www.mendeley.com/research/commd1-promotes-pvhl-o2independent-proteolysis-hif1%CE%B1-via-hsp9070
Events
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Mendeley | Further Information

{"title"=>"COMMD1 promotes pVHL and O2-independent proteolysis of HIF-1α via HSP90/70", "type"=>"journal", "authors"=>[{"first_name"=>"Bart", "last_name"=>"van de Sluis", "scopus_author_id"=>"6602558146"}, {"first_name"=>"Arjan J.", "last_name"=>"Groot", "scopus_author_id"=>"7004233605"}, {"first_name"=>"Jeroen", "last_name"=>"Vermeulen", "scopus_author_id"=>"35219429600"}, {"first_name"=>"Elsken", "last_name"=>"van der Wall", "scopus_author_id"=>"7101764508"}, {"first_name"=>"Paul J.", "last_name"=>"van Diest", "scopus_author_id"=>"7102753018"}, {"first_name"=>"Cisca", "last_name"=>"Wijmenga", "scopus_author_id"=>"7005273061"}, {"first_name"=>"Leo W.", "last_name"=>"Klomp", "scopus_author_id"=>"7004278618"}, {"first_name"=>"Marc", "last_name"=>"Vooijs", "scopus_author_id"=>"6602835614"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-70350012306", "pmid"=>"19802386", "pui"=>"355426566", "isbn"=>"1932-6203 (Electronic)", "sgr"=>"70350012306", "doi"=>"10.1371/journal.pone.0007332", "issn"=>"19326203"}, "id"=>"ac729587-ba6f-37e4-81c6-db8271dd4c89", "abstract"=>"BACKGROUND: The Copper Metabolism MURR1 Domain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-kappaB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for Commd1 have increased expression of hypoxia/HIF-regulated genes i.e. VEGF, PGK and Bnip3. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL. PRINCIPAL FINDINGS: Here we characterized the mechanism by which COMMD1 regulates HIF-1alpha protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90beta for binding to the NH(2)-terminal DNA-binding and heterodimerization domain of HIF-1alpha to regulate HIF-1alpha stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1alpha degradation independent of ubiquitin and pVHL. CONCLUSION/SIGNIFICANCE: These data reveal a novel role for COMMD1 in conjunction with HSP90beta/HSP70 in the ubiquitin and O(2)-independent regulation of HIF-1alpha.", "link"=>"http://www.mendeley.com/research/commd1-promotes-pvhl-o2independent-proteolysis-hif1%CE%B1-via-hsp9070", "reader_count"=>32, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>3, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>3, "Professor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>6, "Chemistry"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}}, "reader_count_by_country"=>{"United States"=>3, "Uruguay"=>1, "United Kingdom"=>1}, "group_count"=>2}

Scopus | Further Information

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  • {"files"=>["https://ndownloader.figshare.com/files/881340"], "description"=>"<p>Under normoxic conditions, newly synthesized HIF-1α binds to HSP70 and HSP90 for proper maturation, but it is immediately degraded by the 26S proteasome after it is hydroxylated and ubiquitinated in a pVHL dependent process. Under hypoxic conditions, HIF-1α is not subjected to hydroxyl- and ubiquitin-dependent degradation and heterodimerizes with HIF-1β, and binds to hypoxia response element (HRE) containing promoters in target genes. Upon reoxygenation HIF-1α is ubiquitinated by pVHL, and COMMD1 is bound to HIF-1α to facilitate proteasomal degradation. Inactivation of HSP90 (e.g. using 17-AAG or Geldanamycin) leads to incorrect folding of HIF-1α and the formation of a heterocomplex with HSP70 and COMMD1, and subsequently degradation by the 20S proteasome. Altogether, in this study we suggest that COMMD1 facilitates the proteasomal degradation of HIF-1α after reoxygenation or HSP90 inhibition independent of posttranslational modification by ubiquitin.</p>", "links"=>[], "tags"=>["commd1-associated"], "article_id"=>551792, "categories"=>["Cell Biology", "Biochemistry"], "users"=>["Bart van de Sluis", "Arjan J. Groot", "Jeroen Vermeulen", "Elsken van der Wall", "Paul J. van Diest", "Cisca Wijmenga", "Leo W. Klomp", "Marc Vooijs"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007332.g005", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_representation_of_the_mechanism_of_COMMD1_associated_HIF_1_945_degradation_/551792", "title"=>"Schematic representation of the mechanism of COMMD1-associated HIF-1α degradation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-10-05 00:29:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/437772", "https://ndownloader.figshare.com/files/437895"], "description"=>"<div><h3>Background</h3><p>The <u>C</u>opper <u>M</u>etabolism <u>M</u>URR1 <u>D</u>omain containing 1 protein COMMD1 has been associated with copper homeostasis, NF-κB signaling, and sodium transport. Recently, we identified COMMD1 as a novel protein in HIF-1 signaling. Mouse embryos deficient for <em>Commd1</em> have increased expression of hypoxia/HIF-regulated genes i.e. <em>VEGF</em>, <em>PGK</em> and <em>Bnip3</em>. Hypoxia-inducible factors (HIFs) are master regulators of oxygen homeostasis, which control angiogenesis, erythropoiesis, glycolysis and cell survival/proliferation under normal and pathologic conditions. Although HIF activity is mainly controlled by ubiquitination and protein degradation by the von Hippel Lindau (pVHL) tumor suppressor gene other mechanisms have recently been identified that regulate HIF signaling independently of pVHL.</p><h3>Principal Findings</h3><p>Here we characterized the mechanism by which COMMD1 regulates HIF-1α protein degradation. We show that COMMD1 competes with the chaperone heat shock protein HSP90β for binding to the NH<sub>2</sub>-terminal DNA-binding and heterodimerization domain of HIF-1α to regulate HIF-1α stability together with HSP70. Inhibition of HSP90 activity with 17-Allylamino-17-demethoxygeldanamycin (17-AAG) increased COMMD1-mediated HIF-1α degradation independent of ubiquitin and pVHL.</p><h3>Conclusion/Significance</h3><p>These data reveal a novel role for COMMD1 in conjunction with HSP90β/HSP70 in the ubiquitin and O<sub>2</sub>-independent regulation of HIF-1α.</p></div>", "links"=>[], "tags"=>["commd1", "promotes", "pvhl", "proteolysis"], "article_id"=>146294, "categories"=>["Cell Biology", "Biochemistry"], "users"=>["Bart van de Sluis", "Arjan J. Groot", "Jeroen Vermeulen", "Elsken van der Wall", "Paul J. van Diest", "Cisca Wijmenga", "Leo W. Klomp", "Marc Vooijs"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0007332.s001", "https://dx.doi.org/10.1371/journal.pone.0007332.s002"], "stats"=>{"downloads"=>4, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/COMMD1_Promotes_pVHL_and_O_2_Independent_Proteolysis_of_HIF_1_via_HSP90_70/146294", "title"=>"COMMD1 Promotes pVHL and O<sub>2</sub>-Independent Proteolysis of HIF-1α via HSP90/70", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-10-05 01:44:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/881073"], "description"=>"<p>(A). HEK 293T cells were transfected with cDNA constructs encoding COMMD1-Ha, Flag-HIF-1α, or Ha-HSP90β with increase amounts of plasmid DNA as indicated. Whole cell lysates were immunoprecipitated with anti-Flag antibody and subjected to Western Blot analysis. (B) Anti-Flag immunprecipitations using HEK 293T whole cells lysates expressing Ha-HSP90β, COMMD1-Ha, Flag-HIF-1α. Prior to cell lysis and immunoprecipitation cells were treated with vehicle, 17-AAG (2 µM, 8 hr), or MG132 (5 µM, 8 hr) as indicated. (C) Cells were cotransfected with Ha-HSP90β, COMMD1-Ha, Flag-HIF-1α. Whole cell lysates were subjected to immunprecipation with anti-Flag antibody. Bands were quantified by densitometry using Quantity One (Bio-Rad) to calculate the quantity of the ratio of precipitated HSP90β relative to the input levels. The percentage of precipitated HSP90β is indicated (D) HEK 293T whole cells lysates expressing Ha-HSP90β, COMMD1-Ha, Flag-HIF-1α (P402A/P564A) were used for immunprecipation with anti-Flag antibody. Prior to cell lysis and immunoprecipitation cells were treated with vehicle or 17-AAG (2 µM, 8 hr). All data represent at least two experiments with comparable results.</p>", "links"=>[], "tags"=>["competes", "commd1", "binding"], "article_id"=>551527, "categories"=>["Cell Biology", "Biochemistry"], "users"=>["Bart van de Sluis", "Arjan J. Groot", "Jeroen Vermeulen", "Elsken van der Wall", "Paul J. van Diest", "Cisca Wijmenga", "Leo W. Klomp", "Marc Vooijs"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007332.g002", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HSP90_946_competes_with_COMMD1_for_binding_to_HIF_1_945_/551527", "title"=>"HSP90β competes with COMMD1 for binding to HIF-1α.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-10-05 00:25:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/881171"], "description"=>"<p>HEK 293T stably overexpressing COMMD1-Flag (OV) and control cells (EV) (A) were transfected with Flag-HIF-1α (P402A/P564A). Cells were untreated or treated with 17-AAG (2 µM) and CHX (40 µg/ml) was added to the cells. HIF-1α levels were determined by Western Blot analysis. Bands were quantified by densitometry using Quantity One (Bio-Rad) to calculate the half-life values (T1/2) of HIF-1α (P402A/P564A). For each sample, mean values±SEM are shown (n = 3), significant difference were determined using a Student <i>t</i>-test, p = 0.0438 (C) Ts20 cells, containing thermolabile ubiquitin activation enzyme E1, were transfected with empty vector or COMMD1-flag. Cells were cultured under permissive temperature (30°C) or nonpermissive temperature (39°C) for 10 hr. Cells were treated with vehicle or 17-AAG for 8 hr prior to cell lysis and western blot analysis. All data represent three experiments with comparable results.</p>", "links"=>[], "tags"=>["proteolysis", "hsp90-dependent", "ubiquitin"], "article_id"=>551624, "categories"=>["Cell Biology", "Biochemistry"], "users"=>["Bart van de Sluis", "Arjan J. Groot", "Jeroen Vermeulen", "Elsken van der Wall", "Paul J. van Diest", "Cisca Wijmenga", "Leo W. Klomp", "Marc Vooijs"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007332.g003", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_COMMD1_increased_HIF_1_945_proteolysis_in_an_HSP90_dependent_but_ubiquitin_independent_manner_/551624", "title"=>"COMMD1 increased HIF-1α proteolysis in an HSP90-dependent but ubiquitin independent manner.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-10-05 00:27:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/880960"], "description"=>"<p>(A) The stability of HIF-1α protein was determined in HeLa COMMD1 knockdown (KD) and control (EV) cells by immunoblotting. After hypoxia (1% O<sub>2</sub>) for 8 hours the cells were reoxygenized (21% O<sub>2</sub>) for the indicated time prior to cell lysis. Post-translational modified HIF-1α, can be seen as high-molecular mass-proteins detected by anti-HIF-1α antibody indicated with asterisks. β-actin expression was used as a loading. (B) The maturation/stability of HIF-1α protein, was determined in HeLa COMMD1 knockdown (KD) and control cells (EV) by immunoblotting. After culturing the cells under normoxic conditions (21% O<sub>2</sub>) cells were exposed to 1% O<sub>2</sub> for the indicated times. HSP90β expression was determined and β-actin expression was used as a loading control. This experiment was repeated three times with similar results.</p>", "links"=>[], "tags"=>["mediates"], "article_id"=>551415, "categories"=>["Cell Biology", "Biochemistry"], "users"=>["Bart van de Sluis", "Arjan J. Groot", "Jeroen Vermeulen", "Elsken van der Wall", "Paul J. van Diest", "Cisca Wijmenga", "Leo W. Klomp", "Marc Vooijs"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007332.g001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_COMMD1_mediates_HIF_1_945_protein_stability_/551415", "title"=>"COMMD1 mediates HIF-1α protein stability.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-10-05 00:23:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/881261"], "description"=>"<p>(<b>Α</b>) HEK 293T whole cells lysates expressing HSP70 and Flag-HIF-1α were used for anti-Flag immunprecipitation. Prior to cell lysis cells were treated with vehicle or 17-AAG (2 µM, 8 hr) as indicated. (B) HEK 293T cells were transfected with plasmids encoding HSP70, COMMD1-Ha and Flag-HIF-1α. Lysates of cells, which were treated with 17-AAG (2 µM, 8 hr), were used for sequential immunoprecipitation. Anti-Flag precipitates were eluted with Flag-peptides and eluates were used for immunoprecipitation with anti-HA antibody. Whole cell lysates, and immunoprecipitates were subjected to Western Blot analysis. (C) Using anti-V5 antibody HSP70 was immunoprecipitated from HEK 293T cell lystates expressing HSP70-V5 and COMMD1-Ha. Whole cell lysates, and precipitates were analyzed by SDS-PAGE and immunoblotting as indicated.</p>", "links"=>[], "tags"=>["forms", "tripartite", "hsp70"], "article_id"=>551708, "categories"=>["Cell Biology", "Biochemistry"], "users"=>["Bart van de Sluis", "Arjan J. Groot", "Jeroen Vermeulen", "Elsken van der Wall", "Paul J. van Diest", "Cisca Wijmenga", "Leo W. Klomp", "Marc Vooijs"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007332.g004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_COMMD1_forms_a_tripartite_complex_with_HSP70_and_HIF_1_945_/551708", "title"=>"COMMD1 forms a tripartite complex with HSP70 and HIF-1α.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-10-05 00:28:28"}

PMC Usage Stats | Further Information

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