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  • 1
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    Frequent inactivation of A20 in B-cell lymphomas (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-05
    Description: A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kato, Motohiro -- Sanada, Masashi -- Kato, Itaru -- Sato, Yasuharu -- Takita, Junko -- Takeuchi, Kengo -- Niwa, Akira -- Chen, Yuyan -- Nakazaki, Kumi -- Nomoto, Junko -- Asakura, Yoshitaka -- Muto, Satsuki -- Tamura, Azusa -- Iio, Mitsuru -- Akatsuka, Yoshiki -- Hayashi, Yasuhide -- Mori, Hiraku -- Igarashi, Takashi -- Kurokawa, Mineo -- Chiba, Shigeru -- Mori, Shigeo -- Ishikawa, Yuichi -- Okamoto, Koji -- Tobinai, Kensei -- Nakagama, Hitoshi -- Nakahata, Tatsutoshi -- Yoshino, Tadashi -- Kobayashi, Yukio -- Ogawa, Seishi -- England -- Nature. 2009 Jun 4;459(7247):712-6. doi: 10.1038/nature07969. Epub 2009 May 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, Department of Pediatrics, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412163" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/physiology ; Cell Line ; Cysteine Endopeptidases/*genetics/*metabolism ; DNA-Binding Proteins ; Gene Expression ; *Gene Silencing ; Genome/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics/*metabolism ; Lymphoma, B-Cell/*genetics/*physiopathology ; Mice ; NF-kappa B/genetics/metabolism ; Nuclear Proteins/*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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  • 2
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    In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-08-13
    Description: Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748827/" 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/PMC2748827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itoh, Yasushi -- Shinya, Kyoko -- Kiso, Maki -- Watanabe, Tokiko -- Sakoda, Yoshihiro -- Hatta, Masato -- Muramoto, Yukiko -- Tamura, Daisuke -- Sakai-Tagawa, Yuko -- Noda, Takeshi -- Sakabe, Saori -- Imai, Masaki -- Hatta, Yasuko -- Watanabe, Shinji -- Li, Chengjun -- Yamada, Shinya -- Fujii, Ken -- Murakami, Shin -- Imai, Hirotaka -- Kakugawa, Satoshi -- Ito, Mutsumi -- Takano, Ryo -- Iwatsuki-Horimoto, Kiyoko -- Shimojima, Masayuki -- Horimoto, Taisuke -- Goto, Hideo -- Takahashi, Kei -- Makino, Akiko -- Ishigaki, Hirohito -- Nakayama, Misako -- Okamatsu, Masatoshi -- Takahashi, Kazuo -- Warshauer, David -- Shult, Peter A -- Saito, Reiko -- Suzuki, Hiroshi -- Furuta, Yousuke -- Yamashita, Makoto -- Mitamura, Keiko -- Nakano, Kunio -- Nakamura, Morio -- Brockman-Schneider, Rebecca -- Mitamura, Hiroshi -- Yamazaki, Masahiko -- Sugaya, Norio -- Suresh, M -- Ozawa, Makoto -- Neumann, Gabriele -- Gern, James -- Kida, Hiroshi -- Ogasawara, Kazumasa -- Kawaoka, Yoshihiro -- HHNSN266200700010C/NS/NINDS NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- HHSN272200800060C/AI/NIAID NIH HHS/ -- R01 AI069274/AI/NIAID NIH HHS/ -- R01 AI069274-04/AI/NIAID NIH HHS/ -- U19 AI070503/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1021-5. doi: 10.1038/nature08260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19672242" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Viral/immunology ; Antiviral Agents/pharmacology ; Cell Line ; Dogs ; Female ; Ferrets/virology ; HN Protein/metabolism ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects/enzymology/pathogenicity/*physiology ; Lung/immunology/pathology/virology ; Macaca fascicularis/immunology/virology ; Male ; Mice ; Mice, Inbred BALB C ; Neutralization Tests ; Orthomyxoviridae Infections/immunology/transmission/virology ; Primate Diseases/pathology/virology ; Swine/*virology ; Swine Diseases/pathology/virology ; Swine, Miniature/virology ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-04-12
    Description: RNA interference (RNAi) is a mechanism by which double-stranded RNAs (dsRNAs) suppress specific transcripts in a sequence-dependent manner. dsRNAs are processed by Dicer to 21-24-nucleotide small interfering RNAs (siRNAs) and then incorporated into the argonaute (Ago) proteins. Gene regulation by endogenous siRNAs has been observed only in organisms possessing RNA-dependent RNA polymerase (RdRP). In mammals, where no RdRP activity has been found, biogenesis and function of endogenous siRNAs remain largely unknown. Here we show, using mouse oocytes, that endogenous siRNAs are derived from naturally occurring dsRNAs and have roles in the regulation of gene expression. By means of deep sequencing, we identify a large number of both approximately 25-27-nucleotide Piwi-interacting RNAs (piRNAs) and approximately 21-nucleotide siRNAs corresponding to messenger RNAs or retrotransposons in growing oocytes. piRNAs are bound to Mili and have a role in the regulation of retrotransposons. siRNAs are exclusively mapped to retrotransposons or other genomic regions that produce transcripts capable of forming dsRNA structures. Inverted repeat structures, bidirectional transcription and antisense transcripts from various loci are sources of the dsRNAs. Some precursor transcripts of siRNAs are derived from expressed pseudogenes, indicating that one role of pseudogenes is to adjust the level of the founding source mRNA through RNAi. Loss of Dicer or Ago2 results in decreased levels of siRNAs and increased levels of retrotransposon and protein-coding transcripts complementary to the siRNAs. Thus, the RNAi pathway regulates both protein-coding transcripts and retrotransposons in mouse oocytes. Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Toshiaki -- Totoki, Yasushi -- Toyoda, Atsushi -- Kaneda, Masahiro -- Kuramochi-Miyagawa, Satomi -- Obata, Yayoi -- Chiba, Hatsune -- Kohara, Yuji -- Kono, Tomohiro -- Nakano, Toru -- Surani, M Azim -- Sakaki, Yoshiyuki -- Sasaki, Hiroyuki -- England -- Nature. 2008 May 22;453(7194):539-43. doi: 10.1038/nature06908. Epub 2008 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima 411-8540, Japan. toshwata@lab.nig.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18404146" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Eukaryotic Initiation Factor-2/deficiency/genetics/metabolism ; Female ; Gene Expression Regulation, Developmental ; Gene Library ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Oocytes/growth & development/*metabolism ; Polymerase Chain Reaction ; Pseudogenes/genetics ; *RNA Interference ; RNA, Double-Stranded/*genetics/*metabolism ; RNA, Messenger/*genetics/metabolism ; RNA, Small Interfering/*genetics/*metabolism ; Retroelements/genetics ; Ribonuclease III/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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  • 4
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    TMEM16A confers receptor-activated calcium-dependent chloride conductance (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-30
    Description: Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Young Duk -- Cho, Hawon -- Koo, Jae Yeon -- Tak, Min Ho -- Cho, Yeongyo -- Shim, Won-Sik -- Park, Seung Pyo -- Lee, Jesun -- Lee, Byeongjun -- Kim, Byung-Moon -- Raouf, Ramin -- Shin, Young Ki -- Oh, Uhtaek -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Oct 30;455(7217):1210-5. doi: 10.1038/nature07313. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sensory Research Center, CRI, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724360" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/*metabolism/pharmacology ; Chloride Channels/chemistry/deficiency/genetics/*metabolism ; Chlorides/*metabolism ; Electric Conductivity ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Intracellular Space/drug effects/metabolism ; Ion Transport/drug effects ; Mice ; Oocytes/metabolism ; Pilocarpine/pharmacology ; RNA, Small Interfering/genetics/metabolism ; Rats ; Receptors, G-Protein-Coupled/*metabolism ; Salivation/drug effects ; Xenopus
    Print ISSN: 0028-0836
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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 pancreatic beta cell mass by neuronal signals from the liver (2008)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2008-11-22
    Description: Metabolic regulation in mammals requires communication between multiple organs and tissues. The rise in the incidence of obesity and associated metabolic disorders, including type 2 diabetes, has renewed interest in interorgan communication. We used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiological compensation for insulin resistance. We found that hepatic activation of extracellular regulated kinase (ERK) signaling induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Imai, Junta -- Katagiri, Hideki -- Yamada, Tetsuya -- Ishigaki, Yasushi -- Suzuki, Toshinobu -- Kudo, Hirohito -- Uno, Kenji -- Hasegawa, Yutaka -- Gao, Junhong -- Kaneko, Keizo -- Ishihara, Hisamitsu -- Niijima, Akira -- Nakazato, Masamitsu -- Asano, Tomoichiro -- Minokoshi, Yasuhiko -- Oka, Yoshitomo -- New York, N.Y. -- Science. 2008 Nov 21;322(5905):1250-4. doi: 10.1126/science.1163971.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19023081" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Proliferation ; Central Nervous System/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Hyperplasia ; Insulin/metabolism ; Insulin Resistance ; Insulin-Secreting Cells/*metabolism/pathology ; Liver/*metabolism ; MAP Kinase Kinase 1/*metabolism ; *MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/*metabolism ; Obesity/*metabolism ; Pancreas/innervation ; Recombinant Proteins/metabolism ; Vagus Nerve/cytology/metabolism ; Xenopus
    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
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    Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function (2005)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2005-08-27
    Description: CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Guangyong -- Guo, Zhong -- Kiniwa, Yukiko -- Voo, Kui Shin -- Peng, Weiyi -- Fu, Tihui -- Wang, Daniel Y -- Li, Yanchun -- Wang, Helen Y -- Wang, Rong-Fu -- P01CA94237/CA/NCI NIH HHS/ -- P50 CA093459/CA/NCI NIH HHS/ -- P50CA58204/CA/NCI NIH HHS/ -- R01CA101795/CA/NCI NIH HHS/ -- R01CA90327/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2005 Aug 26;309(5739):1380-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16123302" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Adoptive Transfer ; Animals ; Antigens, Differentiation/genetics/physiology ; CD4-Positive T-Lymphocytes/*immunology ; Cell Line ; Cell Line, Tumor ; Humans ; Immune Tolerance ; Interleukin-1 Receptor-Associated Kinases ; Killer Cells, Natural/immunology ; Ligands ; Lymphocyte Activation ; Membrane Glycoproteins/genetics/*physiology ; Mice ; Myeloid Differentiation Factor 88 ; Neoplasm Transplantation ; Neoplasms, Experimental/immunology/pathology ; Oligodeoxyribonucleotides/immunology ; Phosphotransferases (Alcohol Group Acceptor)/genetics/physiology ; Poly G/immunology ; RNA Interference ; Receptors, Cell Surface/genetics/*physiology ; Receptors, Immunologic/genetics/physiology ; *Signal Transduction ; T-Lymphocyte Subsets/*immunology ; Toll-Like Receptor 8 ; Toll-Like Receptors
    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
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    TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-28
    Description: T helper cells that produce IL-17 (T(H)17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T(H)17 cells are thought to protect the host from infection, whereas regulatory T (T(reg)) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-beta (TGF-beta), but depends on distinct transcription factors: RORgammat (encoded by Rorc(gammat)) for T(H)17 cells and Foxp3 for T(reg) cells. How TGF-beta regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-beta orchestrates T(H)17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-beta synergizes with interleukin (IL)-6 and IL-21 (refs 9-11) to promote IL-23 receptor (Il23r) expression, favouring T(H)17 cell differentiation. High concentrations of TGF-beta repress IL23r expression and favour Foxp3+ T(reg) cells. RORgammat and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-beta and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-beta-induced Foxp3 inhibits RORgammat function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORgammat alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORgammat, thereby promoting T(H)17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either T(H)17 or T(reg) cells depends on the cytokine-regulated balance of RORgammat and Foxp3.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597437/" 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/PMC2597437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Liang -- Lopes, Jared E -- Chong, Mark M W -- Ivanov, Ivaylo I -- Min, Roy -- Victora, Gabriel D -- Shen, Yuelei -- Du, Jianguang -- Rubtsov, Yuri P -- Rudensky, Alexander Y -- Ziegler, Steven F -- Littman, Dan R -- AI48779/AI/NIAID NIH HHS/ -- R01 AI048779/AI/NIAID NIH HHS/ -- R01 AI048779-05/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 May 8;453(7192):236-40. doi: 10.1038/nature06878. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/drug effects ; Cell Line ; Cells, Cultured ; Forkhead Transcription Factors/genetics/*metabolism ; Gene Expression Regulation/drug effects ; Humans ; Interleukin-17/biosynthesis/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Receptors, Interleukin/genetics/metabolism ; Receptors, Retinoic Acid/*antagonists & inhibitors/genetics/metabolism ; Receptors, Thyroid Hormone/*antagonists & inhibitors/genetics/metabolism ; T-Lymphocytes, Helper-Inducer/*cytology/*drug effects/metabolism ; Transforming Growth Factor beta/*pharmacology
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Oncogenic mutations of ALK kinase in neuroblastoma (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-17
    Description: Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non-Hodgkin's lymphoma (NPM-ALK) and more recently in adenocarcinoma of lung (EML4-ALK), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome-wide scans of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 (33%) neuroblastoma-derived cell lines. All but one mutation in the primary samples (12 out of 13) were found in stages 3-4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild-type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK-specific kinase inhibitors might improve its clinical outcome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Yuyan -- Takita, Junko -- Choi, Young Lim -- Kato, Motohiro -- Ohira, Miki -- Sanada, Masashi -- Wang, Lili -- Soda, Manabu -- Kikuchi, Akira -- Igarashi, Takashi -- Nakagawara, Akira -- Hayashi, Yasuhide -- Mano, Hiroyuki -- Ogawa, Seishi -- England -- Nature. 2008 Oct 16;455(7215):971-4. doi: 10.1038/nature07399.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic ; Chromosomes, Human, Pair 2/genetics ; Fibroblasts ; Gene Dosage/genetics ; Genome, Human/genetics ; Genotype ; Humans ; Mice ; Molecular Sequence Data ; Mutation, Missense/*genetics ; NIH 3T3 Cells ; Neuroblastoma/enzymology/*genetics ; Oligonucleotide Array Sequence Analysis ; Oncogenes/*genetics ; Phosphorylation ; Polymorphism, Single Nucleotide/genetics ; Protein-Tyrosine Kinases/deficiency/*genetics/metabolism ; RNA Interference ; Receptor Protein-Tyrosine Kinases ; Sequence Analysis, DNA ; Signal Transduction
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    DNA demethylation in hormone-induced transcriptional derepression (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-10-16
    Description: Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites ((5m)CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the (5m)CpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4(-/-) mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Mi-Sun -- Kondo, Takeshi -- Takada, Ichiro -- Youn, Min-Young -- Yamamoto, Yoko -- Takahashi, Sayuri -- Matsumoto, Takahiro -- Fujiyama, Sally -- Shirode, Yuko -- Yamaoka, Ikuko -- Kitagawa, Hirochika -- Takeyama, Ken-ichi -- Shibuya, Hiroshi -- Ohtake, Fumiaki -- Kato, Shigeaki -- England -- Nature. 2009 Oct 15;461(7266):1007-12. doi: 10.1038/nature08456.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19829383" target="_blank"〉PubMed〈/a〉
    Keywords: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics ; Animals ; Cell Line ; CpG Islands/genetics ; DNA (Cytosine-5-)-Methyltransferase/metabolism ; DNA Glycosylases/metabolism ; DNA Methylation/*drug effects ; Down-Regulation/drug effects ; Endodeoxyribonucleases/deficiency/genetics ; Mice ; Parathyroid Hormone/*pharmacology ; Phosphorylation ; Protein Kinase C/metabolism ; Response Elements/genetics ; Transcription, Genetic/*drug effects ; Vitamin D/pharmacology
    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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    Dendritic cell apoptosis in the maintenance of immune tolerance (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-02-25
    Description: Apoptosis in the immune system is critical for maintaining self-tolerance and preventing autoimmunity. Nevertheless, inhibiting apoptosis in lymphocytes is not alone sufficient to break self-tolerance, suggesting the involvement of other cell types. We investigated whether apoptosis in dendritic cells (DCs) helps regulate self-tolerance by generating transgenic mice expressing the baculoviral caspase inhibitor, p35, in DCs (DC-p35). DC-p35 mice displayed defective DC apoptosis, resulting in their accumulation and, in turn, chronic lymphocyte activation and systemic autoimmune manifestations. The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Min -- Wang, Yui-Hsi -- Wang, Yihong -- Huang, Li -- Sandoval, Hector -- Liu, Yong-Jun -- Wang, Jin -- New York, N.Y. -- Science. 2006 Feb 24;311(5764):1160-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA. minc@bcm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16497935" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Aging ; Animals ; Antibodies, Antinuclear/analysis ; *Apoptosis ; *Autoimmunity ; B-Lymphocytes/immunology ; Caspase Inhibitors ; Cell Survival ; Dendritic Cells/*immunology/*physiology ; Kidney/immunology ; Lung/immunology ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; *Self Tolerance ; Spleen/immunology ; T-Lymphocytes/immunology ; Viral Proteins/genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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