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  • Mice  (2,147)
  • Molecular Sequence Data  (463)
  • Nature Publishing Group (NPG)  (2,522)
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  • 1
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    IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-04-13
    Description: Interleukin (IL)-17-producing helper T (T(H)17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases. IL-6 and transforming growth factor-beta (TGF-beta) induce T(H)17 development, in which the orphan nuclear receptors, RORgammat and RORalpha, have an indispensable role. However, in the absence of IL-6 and TGF-beta, the ectopic expression of RORgammat or RORalpha leads to only a modest IL-17 production. Here we identify a nuclear IkappaB family member, IkappaBzeta (encoded by the Nfkbiz gene), as a transcription factor required for T(H)17 development in mice. The ectopic expression of IkappaBzeta in naive CD4(+) T cells together with RORgammat or RORalpha potently induces T(H)17 development, even in the absence of IL-6 and TGF-beta. Notably, Nfkbiz(-/-) mice have a defect in T(H)17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IkappaBzeta was clearly demonstrated by the resistance to EAE of the Rag2(-/-) mice into which Nfkbiz(-/-) CD4(+) T cells were transferred. In cooperation with RORgammat and RORalpha, IkappaBzeta enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T(H)17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okamoto, Kazuo -- Iwai, Yoshiko -- Oh-Hora, Masatsugu -- Yamamoto, Masahiro -- Morio, Tomohiro -- Aoki, Kazuhiro -- Ohya, Keiichi -- Jetten, Anton M -- Akira, Shizuo -- Muta, Tatsushi -- Takayanagi, Hiroshi -- Z01-ES-101586/ES/NIEHS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Apr 29;464(7293):1381-5. doi: 10.1038/nature08922. Epub 2010 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20383124" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Coculture Techniques ; Dendritic Cells/cytology/immunology ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; *Gene Expression Regulation ; Interleukin-17/biosynthesis/genetics/*metabolism ; Mice ; NF-kappa B p50 Subunit/metabolism ; Nuclear Proteins/deficiency/genetics/*metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 1/genetics/*metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics/*metabolism ; Promoter Regions, Genetic/genetics ; T-Lymphocytes, Helper-Inducer/*cytology/*metabolism ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Control of female gamete formation by a small RNA pathway in Arabidopsis (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-03-09
    Description: In the ovules of most sexual flowering plants female gametogenesis is initiated from a single surviving gametic cell, the functional megaspore, formed after meiosis of the somatically derived megaspore mother cell (MMC). Because some mutants and certain sexual species exhibit more than one MMC, and many others are able to form gametes without meiosis (by apomixis), it has been suggested that somatic cells in the ovule are competent to respond to a local signal likely to have an important function in determination. Here we show that the Arabidopsis protein ARGONAUTE 9 (AGO9) controls female gamete formation by restricting the specification of gametophyte precursors in a dosage-dependent, non-cell-autonomous manner. Mutations in AGO9 lead to the differentiation of multiple gametic cells that are able to initiate gametogenesis. The AGO9 protein is not expressed in the gamete lineage; instead, it is expressed in cytoplasmic foci of somatic companion cells. Mutations in SUPPRESSOR OF GENE SILENCING 3 and RNA-DEPENDENT RNA POLYMERASE 6 exhibit an identical defect to ago9 mutants, indicating that the movement of small RNA (sRNAs) silencing out of somatic companion cells is necessary for controlling the specification of gametic cells. AGO9 preferentially interacts with 24-nucleotide sRNAs derived from transposable elements (TEs), and its activity is necessary to silence TEs in female gametes and their accessory cells. Our results show that AGO9-dependent sRNA silencing is crucial to specify cell fate in the Arabidopsis ovule, and that epigenetic reprogramming in companion cells is necessary for sRNA-dependent silencing in plant gametes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613780/" 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/PMC4613780/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olmedo-Monfil, Vianey -- Duran-Figueroa, Noe -- Arteaga-Vazquez, Mario -- Demesa-Arevalo, Edgar -- Autran, Daphne -- Grimanelli, Daniel -- Slotkin, R Keith -- Martienssen, Robert A -- Vielle-Calzada, Jean-Philippe -- R01 GM067014/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 25;464(7288):628-32. doi: 10.1038/nature08828. Epub 2010 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Grupo de Desarrollo Reproductivo y Apomixis, Laboratorio Nacional de Genomica para la Biodiversidad y Departamento de Ingenieria Genetica de Plantas, Cinvestav Irapuato CP36500 Guanajuato, Mexico.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20208518" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/genetics/growth & development/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Argonaute Proteins ; DNA Transposable Elements/genetics ; Gametogenesis, Plant/*physiology ; Gene Expression Regulation, Plant ; Gene Silencing ; Meiosis ; Molecular Sequence Data ; Mutagenesis, Insertional/genetics ; Ovule/growth & development/*metabolism ; Phenotype ; RNA, Plant/*metabolism ; RNA-Binding Proteins/genetics/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Active site remodelling accompanies thioester bond formation in the SUMO E1 (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-19
    Description: E1 enzymes activate ubiquitin (Ub) and ubiquitin-like (Ubl) proteins in two steps by carboxy-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1 Cys domain. The structural basis for these intermediates remains unknown. Here we report crystal structures for human SUMO E1 in complex with SUMO adenylate and tetrahedral intermediate analogues at 2.45 and 2.6 A, respectively. These structures show that side chain contacts to ATP.Mg are released after adenylation to facilitate a 130 degree rotation of the Cys domain during thioester bond formation that is accompanied by remodelling of key structural elements including the helix that contains the E1 catalytic cysteine, the crossover and re-entry loops, and refolding of two helices that are required for adenylation. These changes displace side chains required for adenylation with side chains required for thioester bond formation. Mutational and biochemical analyses indicate these mechanisms are conserved in other E1s.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866016/" 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/PMC2866016/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olsen, Shaun K -- Capili, Allan D -- Lu, Xuequan -- Tan, Derek S -- Lima, Christopher D -- F32 GM075695/GM/NIGMS NIH HHS/ -- F32 GM075695-03/GM/NIGMS NIH HHS/ -- R01 AI068038/AI/NIAID NIH HHS/ -- R01 AI068038-02/AI/NIAID NIH HHS/ -- R01 AI068038-03/AI/NIAID NIH HHS/ -- R01 GM065872/GM/NIGMS NIH HHS/ -- R01 GM065872-09/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):906-12. doi: 10.1038/nature08765.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164921" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; *Biocatalysis ; Catalytic Domain/*physiology ; Conserved Sequence ; Crystallography, X-Ray ; Cysteine/chemistry/metabolism ; Humans ; Magnesium/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; SUMO-1 Protein/*chemistry/*metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Sulfides/*metabolism ; Ubiquitin/metabolism ; Ubiquitin-Activating Enzymes/*chemistry/*metabolism ; Ubiquitins/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-20
    Description: DNA methylation is one of the best-characterized epigenetic modifications. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491567/" 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/PMC3491567/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Shinsuke -- D'Alessio, Ana C -- Taranova, Olena V -- Hong, Kwonho -- Sowers, Lawrence C -- Zhang, Yi -- CA084487/CA/NCI NIH HHS/ -- GM68804/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 26;466(7310):1129-33. doi: 10.1038/nature09303.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20639862" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/*metabolism ; Alkaline Phosphatase/metabolism ; Animals ; Blastocyst Inner Cell Mass/*metabolism ; Cell Proliferation ; Cytosine/*analogs & derivatives/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Embryonic Stem Cells/*cytology ; Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Homeodomain Proteins/metabolism ; Mice ; Proto-Oncogene Proteins/genetics/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Regulation of myeloid leukaemia by the cell-fate determinant Musashi (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-20
    Description: Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918284/" 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/PMC2918284/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takahiro -- Kwon, Hyog Young -- Zimdahl, Bryan -- Congdon, Kendra L -- Blum, Jordan -- Lento, William E -- Zhao, Chen -- Lagoo, Anand -- Gerrard, Gareth -- Foroni, Letizia -- Goldman, John -- Goh, Harriet -- Kim, Soo-Hyun -- Kim, Dong-Wook -- Chuah, Charles -- Oehler, Vivian G -- Radich, Jerald P -- Jordan, Craig T -- Reya, Tannishtha -- AI067798/AI/NIAID NIH HHS/ -- CA122206/CA/NCI NIH HHS/ -- CA140371/CA/NCI NIH HHS/ -- CA18029/CA/NCI NIH HHS/ -- DK072234/DK/NIDDK NIH HHS/ -- DK63031/DK/NIDDK NIH HHS/ -- DP1 CA174422/CA/NCI NIH HHS/ -- DP1 OD006430/OD/NIH HHS/ -- DP1 OD006430-01/OD/NIH HHS/ -- DP1 OD006430-02/OD/NIH HHS/ -- DP1OD006430/OD/NIH HHS/ -- HL097767/HL/NHLBI NIH HHS/ -- P01 CA018029/CA/NCI NIH HHS/ -- R01 CA140371/CA/NCI NIH HHS/ -- R01 DK063031/DK/NIDDK NIH HHS/ -- R01 DK063031-01/DK/NIDDK NIH HHS/ -- R01 DK063031-01S1/DK/NIDDK NIH HHS/ -- R01 DK063031-02/DK/NIDDK NIH HHS/ -- R01 DK063031-03/DK/NIDDK NIH HHS/ -- R01 DK063031-04/DK/NIDDK NIH HHS/ -- R01 DK063031-05/DK/NIDDK NIH HHS/ -- R01 DK063031-06/DK/NIDDK NIH HHS/ -- R01 DK063031-07/DK/NIDDK NIH HHS/ -- R01 DK063031-07S1/DK/NIDDK NIH HHS/ -- R01 DK063031-08/DK/NIDDK NIH HHS/ -- R01 DK072234/DK/NIDDK NIH HHS/ -- R01 DK072234-01A1/DK/NIDDK NIH HHS/ -- R01 DK072234-02/DK/NIDDK NIH HHS/ -- R01 DK072234-03/DK/NIDDK NIH HHS/ -- R01 DK072234-04/DK/NIDDK NIH HHS/ -- R01 HL097767/HL/NHLBI NIH HHS/ -- R01 HL097767-01/HL/NHLBI NIH HHS/ -- R01 HL097767-02/HL/NHLBI NIH HHS/ -- T32 GM007184-33/GM/NIGMS NIH HHS/ -- U19 AI067798/AI/NIAID NIH HHS/ -- U19 AI067798-010006/AI/NIAID NIH HHS/ -- U19 AI067798-020006/AI/NIAID NIH HHS/ -- U19 AI067798-030006/AI/NIAID NIH HHS/ -- U19 AI067798-040006/AI/NIAID NIH HHS/ -- U19 AI067798-050006/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):765-8. doi: 10.1038/nature09171. Epub 2010 Jul 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20639863" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blast Crisis/genetics/metabolism/pathology ; *Cell Differentiation/genetics ; Disease Progression ; Fusion Proteins, bcr-abl/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Homeodomain Proteins/genetics/metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/*metabolism/*pathology ; Membrane Proteins/biosynthesis/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/biosynthesis/genetics/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; Oncogene Proteins, Fusion/genetics/metabolism ; Prognosis ; RNA-Binding Proteins/biosynthesis/genetics/*metabolism ; Receptor, Notch1/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
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  • 6
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    Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-05-14
    Description: The main reason why tumours are not controlled by the immune system is that, unlike pathogens, they do not express potent tumour rejection antigens (TRAs). Tumour vaccination aims at stimulating a systemic immune response targeted to, mostly weak, antigens expressed in the disseminated tumour lesions. Main challenges in developing effective vaccination protocols are the identification of potent and broadly expressed TRAs and effective adjuvants to stimulate a robust and durable immune response. Here we describe an alternative approach in which the expression of new, and thereby potent, antigens are induced in tumour cells by inhibiting nonsense-mediated messenger RNA decay (NMD). Small interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the expression of new antigenic determinants and their immune-mediated rejection. In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation. Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumours leading to their immune recognition and rejection. The cell-free chemically synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107067/" 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/PMC3107067/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pastor, Fernando -- Kolonias, Despina -- Giangrande, Paloma H -- Gilboa, Eli -- R01 CA138503/CA/NCI NIH HHS/ -- R01 CA151857-02/CA/NCI NIH HHS/ -- England -- Nature. 2010 May 13;465(7295):227-30. doi: 10.1038/nature08999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, University of Miami Miller School of Medicine Miami, Florida 33134, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463739" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/*genetics/*immunology ; Aptamers, Nucleotide/genetics ; Cancer Vaccines/genetics/immunology/metabolism ; Carrier Proteins/genetics ; Cell Line, Tumor ; Chickens/genetics ; Colonic Neoplasms/*genetics/*immunology/pathology ; Gene Expression Regulation, Neoplastic ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; RNA Interference ; RNA Stability/*genetics ; RNA, Small Interfering/*genetics/therapeutic use ; Xenograft Model Antitumor Assays
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  • 7
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    Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-03
    Description: The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases. Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058342/" 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/PMC3058342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gan, Boyi -- Hu, Jian -- Jiang, Shan -- Liu, Yingchun -- Sahin, Ergun -- Zhuang, Li -- Fletcher-Sananikone, Eliot -- Colla, Simona -- Wang, Y Alan -- Chin, Lynda -- Depinho, Ronald A -- 01CA141508/CA/NCI NIH HHS/ -- R21 CA135057/CA/NCI NIH HHS/ -- R21 CA135057-01/CA/NCI NIH HHS/ -- R21CA135057/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 2;468(7324):701-4. doi: 10.1038/nature09595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Cell Cycle/*physiology ; Cell Proliferation ; Cell Survival ; *Energy Metabolism ; Female ; Gene Deletion ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/*metabolism/pathology ; *Homeostasis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism/pathology ; Multiprotein Complexes ; Pancytopenia/genetics ; Phenotype ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Proteins/metabolism ; Survival Analysis ; TOR Serine-Threonine Kinases ; Transcription Factors/metabolism
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  • 8
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    A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-05-21
    Description: Type II topoisomerases are required for the management of DNA tangles and supercoils, and are targets of clinical antibiotics and anti-cancer agents. These enzymes catalyse the ATP-dependent passage of one DNA duplex (the transport or T-segment) through a transient, double-stranded break in another (the gate or G-segment), navigating DNA through the protein using a set of dissociable internal interfaces, or 'gates'. For more than 20 years, it has been established that a pair of dimer-related tyrosines, together with divalent cations, catalyse G-segment cleavage. Recent efforts have proposed that strand scission relies on a 'two-metal mechanism', a ubiquitous biochemical strategy that supports vital cellular processes ranging from DNA synthesis to RNA self-splicing. Here we present the structure of the DNA-binding and cleavage core of Saccharomyces cerevisiae topoisomerase II covalently linked to DNA through its active-site tyrosine at 2.5A resolution, revealing for the first time the organization of a cleavage-competent type II topoisomerase configuration. Unexpectedly, metal-soaking experiments indicate that cleavage is catalysed by a novel variation of the classic two-metal approach. Comparative analyses extend this scheme to explain how distantly-related type IA topoisomerases cleave single-stranded DNA, unifying the cleavage mechanisms for these two essential enzyme families. The structure also highlights a hitherto undiscovered allosteric relay that actuates a molecular 'trapdoor' to prevent subunit dissociation during cleavage. This connection illustrates how an indispensable chromosome-disentangling machine auto-regulates DNA breakage to prevent the aberrant formation of mutagenic and cytotoxic genomic lesions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882514/" 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/PMC2882514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Bryan H -- Burgin, Alex B -- Deweese, Joseph E -- Osheroff, Neil -- Berger, James M -- CA077373/CA/NCI NIH HHS/ -- GM033944/GM/NIGMS NIH HHS/ -- GM053960/GM/NIGMS NIH HHS/ -- GM08295/GM/NIGMS NIH HHS/ -- R01 CA077373/CA/NCI NIH HHS/ -- R01 CA077373-11S1/CA/NCI NIH HHS/ -- R01 CA077373-12/CA/NCI NIH HHS/ -- R01 GM033944/GM/NIGMS NIH HHS/ -- T32 CA009592/CA/NCI NIH HHS/ -- T32CA09592/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jun 3;465(7298):641-4. doi: 10.1038/nature08974.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485342" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; DNA/*chemistry/genetics/*metabolism ; DNA Topoisomerases, Type I/*chemistry/*metabolism ; DNA Topoisomerases, Type II/*chemistry/*metabolism ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Saccharomyces cerevisiae/*enzymology ; Tyrosine
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Antagonistic coevolution accelerates molecular evolution (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-26
    Description: The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation. Although the divergence observed at some host-resistance and parasite-infectivity genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Phi2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717453/" 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/PMC3717453/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paterson, Steve -- Vogwill, Tom -- Buckling, Angus -- Benmayor, Rebecca -- Spiers, Andrew J -- Thomson, Nicholas R -- Quail, Mike -- Smith, Frances -- Walker, Danielle -- Libberton, Ben -- Fenton, Andrew -- Hall, Neil -- Brockhurst, Michael A -- 079643/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Mar 11;464(7286):275-8. doi: 10.1038/nature08798. Epub 2010 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences, Biosciences Building, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20182425" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophages/genetics/*physiology ; *Biological Evolution ; *Evolution, Molecular ; Genetic Variation ; Molecular Sequence Data ; Phenotype ; Pseudomonas fluorescens/*genetics/*virology ; Selection, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-19
    Description: Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karlas, Alexander -- Machuy, Nikolaus -- Shin, Yujin -- Pleissner, Klaus-Peter -- Artarini, Anita -- Heuer, Dagmar -- Becker, Daniel -- Khalil, Hany -- Ogilvie, Lesley A -- Hess, Simone -- Maurer, Andre P -- Muller, Elke -- Wolff, Thorsten -- Rudel, Thomas -- Meyer, Thomas F -- England -- Nature. 2010 Feb 11;463(7282):818-22. doi: 10.1038/nature08760. Epub 2010 Jan 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Max Planck Institute for Infection Biology, Chariteplatz 1, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20081832" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Factors/genetics/metabolism ; Cell Line ; Cells, Cultured ; Chick Embryo ; Cyclin-Dependent Kinase Inhibitor p27/deficiency/genetics/metabolism ; Epithelial Cells/virology ; Genome, Human/genetics ; *Host-Pathogen Interactions/genetics/physiology ; Humans ; Influenza A Virus, H1N1 Subtype/classification/*growth & development ; Influenza, Human/*genetics/*virology ; Lung/cytology ; Mice ; Mice, Inbred C57BL ; Protein-Serine-Threonine Kinases/genetics ; Protein-Tyrosine Kinases/genetics ; *RNA Interference ; Virus Replication/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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