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  • 1
    Publication Date: 2012-11-09
    Description: Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" 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/PMC3504625/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Dhvanit I -- Takahashi-Makise, Naoko -- Cooney, Jeffrey D -- Li, Liangtao -- Schultz, Iman J -- Pierce, Eric L -- Narla, Anupama -- Seguin, Alexandra -- Hattangadi, Shilpa M -- Medlock, Amy E -- Langer, Nathaniel B -- Dailey, Tamara A -- Hurst, Slater N -- Faccenda, Danilo -- Wiwczar, Jessica M -- Heggers, Spencer K -- Vogin, Guillaume -- Chen, Wen -- Chen, Caiyong -- Campagna, Dean R -- Brugnara, Carlo -- Zhou, Yi -- Ebert, Benjamin L -- Danial, Nika N -- Fleming, Mark D -- Ward, Diane M -- Campanella, Michelangelo -- Dailey, Harry A -- Kaplan, Jerry -- Paw, Barry H -- K01 DK085217/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- P30 DK072437/DK/NIDDK NIH HHS/ -- R01 DK052380/DK/NIDDK NIH HHS/ -- R01 DK070838/DK/NIDDK NIH HHS/ -- R01 DK096051/DK/NIDDK NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):608-12. doi: 10.1038/nature11536. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135403" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia, Sideroblastic/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Erythroblasts/cytology/*metabolism ; *Erythropoiesis ; Ferrochelatase/metabolism ; Genetic Complementation Test ; Heme/*biosynthesis ; Humans ; Hydrogen-Ion Concentration ; Mice ; Mitochondria/*metabolism/pathology ; Mitochondrial Proteins/deficiency/genetics/*metabolism ; Oxidation-Reduction ; Proteins/genetics/*metabolism ; Zebrafish/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 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
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  • 3
    Publication Date: 2011-10-15
    Description: Persistence of human fetal hemoglobin (HbF, alpha(2)gamma(2)) in adults lessens the severity of sickle cell disease (SCD) and the beta-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of gamma-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746545/" 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/PMC3746545/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Jian -- Peng, Cong -- Sankaran, Vijay G -- Shao, Zhen -- Esrick, Erica B -- Chong, Bryan G -- Ippolito, Gregory C -- Fujiwara, Yuko -- Ebert, Benjamin L -- Tucker, Philip W -- Orkin, Stuart H -- K01 DK093543/DK/NIDDK NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Nov 18;334(6058):993-6. doi: 10.1126/science.1211053. Epub 2011 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21998251" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia, Sickle Cell/blood/*genetics/pathology/*therapy ; Animals ; Carrier Proteins/genetics/*physiology ; DNA Methylation ; Embryo, Mammalian ; Epigenesis, Genetic ; Erythroid Cells/metabolism ; Fetal Hemoglobin/*genetics/metabolism ; *Gene Expression Regulation ; *Gene Silencing ; Histones/metabolism ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Molecular Targeted Therapy ; Nuclear Proteins/genetics/*physiology ; gamma-Globins/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    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
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  • 5
    Publication Date: 2013-02-09
    Description: Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836459/" 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/PMC3836459/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Losman, Julie-Aurore -- Looper, Ryan E -- Koivunen, Peppi -- Lee, Sungwoo -- Schneider, Rebekka K -- McMahon, Christine -- Cowley, Glenn S -- Root, David E -- Ebert, Benjamin L -- Kaelin, William G Jr -- P30 DK049216/DK/NIDDK NIH HHS/ -- R01 CA068490/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Mar 29;339(6127):1621-5. doi: 10.1126/science.1231677. Epub 2013 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393090" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; Glutarates/*metabolism ; *Hematopoiesis ; Humans ; Isocitrate Dehydrogenase/genetics/*metabolism ; Leukemia/*enzymology/genetics ; Models, Biological ; Procollagen-Proline Dioxygenase/*antagonists & inhibitors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2013-12-03
    Description: Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077049/" 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/PMC4077049/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kronke, Jan -- Udeshi, Namrata D -- Narla, Anupama -- Grauman, Peter -- Hurst, Slater N -- McConkey, Marie -- Svinkina, Tanya -- Heckl, Dirk -- Comer, Eamon -- Li, Xiaoyu -- Ciarlo, Christie -- Hartman, Emily -- Munshi, Nikhil -- Schenone, Monica -- Schreiber, Stuart L -- Carr, Steven A -- Ebert, Benjamin L -- P01 CA078378/CA/NCI NIH HHS/ -- P01 CA108631/CA/NCI NIH HHS/ -- P01 CA155258/CA/NCI NIH HHS/ -- P50 CA100707/CA/NCI NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- R01HL082945/HL/NHLBI NIH HHS/ -- RL1- HG004671/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):301-5. doi: 10.1126/science.1244851. Epub 2013 Nov 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Brigham and Women's Hospital, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24292625" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; HEK293 Cells ; Humans ; Ikaros Transcription Factor/genetics/*metabolism ; Interleukin-2/biosynthesis ; Multiple Myeloma/*metabolism ; Proteolysis ; T-Lymphocytes/drug effects/metabolism ; Thalidomide/*analogs & derivatives/pharmacology ; Ubiquitination
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2013-12-18
    Description: The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089965/" 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/PMC4089965/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shalem, Ophir -- Sanjana, Neville E -- Hartenian, Ella -- Shi, Xi -- Scott, David A -- Mikkelsen, Tarjei S -- Heckl, Dirk -- Ebert, Benjamin L -- Root, David E -- Doench, John G -- Zhang, Feng -- 1DP1-MH100706/DP/NCCDPHP CDC HHS/ -- 1R01-DK097768/DK/NIDDK NIH HHS/ -- DP1 MH100706/MH/NIMH NIH HHS/ -- R01 DK097768/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 3;343(6166):84-7. doi: 10.1126/science.1247005. Epub 2013 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336571" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Caspase 9/*genetics ; Cell Survival/*genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Cullin Proteins/genetics ; Drug Resistance, Neoplasm/*genetics ; Gene Knockout Techniques ; Gene Library ; Genes, Neurofibromatosis 1 ; Genes, Neurofibromatosis 2 ; Genetic Loci ; Genetic Testing/*methods ; Genome-Wide Association Study ; Humans ; Indoles/therapeutic use ; Lentivirus ; Mediator Complex/genetics ; Melanoma/drug therapy/*genetics ; Pluripotent Stem Cells/*metabolism ; Protein Kinase Inhibitors/therapeutic use ; Selection, Genetic ; Sulfonamides/therapeutic use ; Transcription Factors/genetics ; raf Kinases/antagonists & inhibitors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2018-11-02
    Description: The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys 2 -His 2 (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4 CRBN E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.
    Keywords: Medicine, Diseases, Molecular Biology, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2018-09-21
    Description: Lenalidomide mediates the ubiquitination and degradation of Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and casein kinase 1α (CK1α) by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4 CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment of multiple myeloma and myelodysplastic syndrome (MDS) with deletion of chromosome 5q [del(5q) MDS]. To identify the cellular machinery required for lenalidomide-induced CRL4 CRBN activity, we performed a positive selection, genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) screen in a lenalidomide-sensitive myeloma cell line. CRBN was the top-ranking gene, with all CRBN -targeting guide RNAs (gRNAs) ranking as the 6 highest-scoring gRNAs. A counterscreen using an IKZF3 degron reporter to assay lenalidomide-induced protein degradation highlighted regulators of cullin-RING ligase neddylation and 2 E2 ubiquitin-conjugating enzymes as necessary for efficient lenalidomide-induced protein degradation. We demonstrated that loss of UBE2M or members of the constitutive photomorphogenesis 9 (COP9) signalosome results in altered neddylation of cullin 4A and impairs lenalidomide-dependent CRL4 CRBN activity. Additionally, we established that UBE2D3 and UBE2G1 play distinct roles in substrate ubiquitination by CRL4 CRBN , with UBE2D3 acting to prime targets via monoubiquitination and UBE2G1 functioning to extend polyubiquitin chains with lysine 48 linkages. The validation of UBE2D3 and UBE2G1 highlights the functional capacity of CRISPR-Cas9 screening to identify E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase complex pairings. More broadly, these findings establish key proteins required for lenalidomide-dependent CRL4 CRBN function in myeloma and inform potential mechanisms of drug resistance.
    Keywords: Myeloid Neoplasia, Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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