Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Publication Date: 2011-02-19
    Description: Toll-like receptors (TLRs) function as initiators of inflammation through their ability to sense pathogen-associated molecular patterns and products of tissue damage. Transcriptional activation of many TLR-responsive genes requires an initial de-repression step in which nuclear receptor co-repressor (NCoR) complexes are actively removed from the promoters of target genes to relieve basal repression. Ligand-dependent SUMOylation of liver X receptors (LXRs) has been found to suppress TLR4-induced transcription potently by preventing the NCoR clearance step, but the underlying mechanisms remain enigmatic. Here we provide evidence that coronin 2A (CORO2A), a component of the NCoR complex of previously unknown function, mediates TLR-induced NCoR turnover by a mechanism involving interaction with oligomeric nuclear actin. SUMOylated LXRs block NCoR turnover by binding to a conserved SUMO2/SUMO3-interaction motif in CORO2A and preventing actin recruitment. Intriguingly, the LXR transrepression pathway can itself be inactivated by inflammatory signals that induce calcium/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma)-dependent phosphorylation of LXRs, leading to their deSUMOylation by the SUMO protease SENP3 and release from CORO2A. These findings uncover a CORO2A-actin-dependent mechanism for the de-repression of inflammatory response genes that can be differentially regulated by phosphorylation and by nuclear receptor signalling pathways that control immunity and homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464905/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Wendy -- Ghisletti, Serena -- Saijo, Kaoru -- Gandhi, Meghal -- Aouadi, Myriam -- Tesz, Greg J -- Zhang, Dawn X -- Yao, Joyee -- Czech, Michael P -- Goode, Bruce L -- Rosenfeld, Michael G -- Glass, Christopher K -- 1F31DK083913/DK/NIDDK NIH HHS/ -- CA52599/CA/NCI NIH HHS/ -- DK074868/DK/NIDDK NIH HHS/ -- DK085853/DK/NIDDK NIH HHS/ -- HC088093/HC/NHLBI NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P50 HL056989/HL/NHLBI NIH HHS/ -- R01 CA052599/CA/NCI NIH HHS/ -- R01 CA097134/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 17;470(7334):414-8. doi: 10.1038/nature09703.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331046" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/chemistry/*metabolism ; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cell Line ; *Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; HeLa Cells ; Homeostasis/genetics ; Humans ; Inflammation/*genetics ; Lipopolysaccharides/pharmacology ; Mice ; Microfilament Proteins/chemistry/deficiency/genetics/*metabolism ; Orphan Nuclear Receptors/metabolism ; Peptide Hydrolases/metabolism ; Peritonitis/chemically induced/metabolism ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Structure, Tertiary ; Signal Transduction ; Sumoylation ; Thioglycolates/pharmacology ; Toll-Like Receptors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2012-07-24
    Description: The identification of somatic activating mutations in JAK2 (refs 1-4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991463/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991463/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koppikar, Priya -- Bhagwat, Neha -- Kilpivaara, Outi -- Manshouri, Taghi -- Adli, Mazhar -- Hricik, Todd -- Liu, Fan -- Saunders, Lindsay M -- Mullally, Ann -- Abdel-Wahab, Omar -- Leung, Laura -- Weinstein, Abby -- Marubayashi, Sachie -- Goel, Aviva -- Gonen, Mithat -- Estrov, Zeev -- Ebert, Benjamin L -- Chiosis, Gabriela -- Nimer, Stephen D -- Bernstein, Bradley E -- Verstovsek, Srdan -- Levine, Ross L -- 1R01CA151949-01/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA151949/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Sep 6;489(7414):155-9. doi: 10.1038/nature11303.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22820254" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Disease Models, Animal ; Drug Resistance, Neoplasm/drug effects ; Enzyme Activation/drug effects ; Gene Knockdown Techniques ; Granulocytes/drug effects/enzymology/metabolism ; HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism ; Humans ; Janus Kinase 1/biosynthesis/deficiency/genetics/metabolism ; Janus Kinase 2/*antagonists & inhibitors/deficiency/genetics/*metabolism ; Mice ; Myeloproliferative Disorders/*drug therapy/enzymology/metabolism/pathology ; Phosphorylation ; Protein Biosynthesis ; *Protein Multimerization ; RNA Interference ; STAT Transcription Factors/*metabolism ; *Signal Transduction/drug effects ; TYK2 Kinase/biosynthesis/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Publication Date: 2015-07-02
    Description: Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1alpha) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1alpha degradation. CK1alpha is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1alpha. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kronke, Jan -- Fink, Emma C -- Hollenbach, Paul W -- MacBeth, Kyle J -- Hurst, Slater N -- Udeshi, Namrata D -- Chamberlain, Philip P -- Mani, D R -- Man, Hon Wah -- Gandhi, Anita K -- Svinkina, Tanya -- Schneider, Rebekka K -- McConkey, Marie -- Jaras, Marcus -- Griffiths, Elizabeth -- Wetzler, Meir -- Bullinger, Lars -- Cathers, Brian E -- Carr, Steven A -- Chopra, Rajesh -- Ebert, Benjamin L -- P01 CA066996/CA/NCI NIH HHS/ -- P01CA108631/CA/NCI NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- R01HL082945/HL/NHLBI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 9;523(7559):183-8. doi: 10.1038/nature14610. Epub 2015 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts 02115, USA [2] University Hospital of Ulm, Department of Internal Medicine III, 89081 Ulm, Germany [3] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts 02115, USA [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Celgene Corporation, San Diego, California 92121, USA. ; Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Roswell Park Cancer Institute, Buffalo, New York 14263, USA. ; University Hospital of Ulm, Department of Internal Medicine III, 89081 Ulm, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26131937" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Casein Kinase I/genetics/*metabolism ; Cell Line ; Gene Expression Regulation/drug effects ; HEK293 Cells ; Humans ; Immunologic Factors/pharmacology ; Jurkat Cells ; K562 Cells ; Mice ; Molecular Sequence Data ; Myelodysplastic Syndromes/*genetics/*physiopathology ; Peptide Hydrolases/chemistry ; Proteolysis/drug effects ; Sequence Alignment ; Sequence Deletion ; Species Specificity ; Thalidomide/*analogs & derivatives/pharmacology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination/*drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Publication Date: 2013-07-23
    Description: Fusion of myoblasts is essential for the formation of multi-nucleated muscle fibres. However, the identity of muscle-specific proteins that directly govern this fusion process in mammals has remained elusive. Here we identify a muscle-specific membrane protein, named myomaker, that controls myoblast fusion. Myomaker is expressed on the cell surface of myoblasts during fusion and is downregulated thereafter. Overexpression of myomaker in myoblasts markedly enhances fusion, and genetic disruption of myomaker in mice causes perinatal death due to an absence of multi-nucleated muscle fibres. Remarkably, forced expression of myomaker in fibroblasts promotes fusion with myoblasts, demonstrating the direct participation of this protein in the fusion process. Pharmacological perturbation of the actin cytoskeleton abolishes the activity of myomaker, consistent with previous studies implicating actin dynamics in myoblast fusion. These findings reveal a long-sought myogenic fusion protein that controls mammalian myoblast fusion and provide new insights into the molecular underpinnings of muscle formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739301/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739301/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Millay, Douglas P -- O'Rourke, Jason R -- Sutherland, Lillian B -- Bezprozvannaya, Svetlana -- Shelton, John M -- Bassel-Duby, Rhonda -- Olson, Eric N -- F32 AR059484/AR/NIAMS NIH HHS/ -- F32AR05948403/AR/NIAMS NIH HHS/ -- HL-077439/HL/NHLBI NIH HHS/ -- HL-111665/HL/NHLBI NIH HHS/ -- HL093039/HL/NHLBI NIH HHS/ -- R01 HL093039/HL/NHLBI NIH HHS/ -- R01 HL111665/HL/NHLBI NIH HHS/ -- U01-HL-100401/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Jul 18;499(7458):301-5. doi: 10.1038/nature12343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23868259" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Fusion ; Cell Line ; Membrane Proteins/genetics/metabolism/*physiology ; Mice ; Mice, Knockout ; *Muscle Development ; Muscle Proteins/genetics/metabolism/*physiology ; Muscle, Skeletal/cytology/*embryology/metabolism ; Myoblasts/*cytology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...