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  • 1
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    Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-01-15
    Description: Phosphoinositide 3-kinase (PI3K) activation has been implicated in many cellular responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function is not clear. The mouse gene encoding the PI3K adapter subunit p85alpha and its splice variants p55alpha and p50alpha was disrupted. Most p85alpha-p55alpha-p50alpha-/- mice die within days after birth. Lymphocyte development and function was studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation and decreased survival after incubation with interleukin-4. In contrast, T cell development and proliferation was normal. This phenotype is similar to defects observed in mice lacking the tyrosine kinase Btk.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fruman, D A -- Snapper, S B -- Yballe, C M -- Davidson, L -- Yu, J Y -- Alt, F W -- Cantley, L C -- R01 GM041890/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1999 Jan 15;283(5400):393-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. dfruman@bidmc.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9888855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD45/analysis ; Apoptosis ; B-Lymphocytes/cytology/enzymology/*immunology ; Catalytic Domain ; Cell Cycle ; Chimera ; Chromones/pharmacology ; Enzyme Inhibitors/pharmacology ; Female ; Gene Targeting ; Immunoglobulins/*blood ; *Lymphocyte Activation ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Morpholines/pharmacology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors/genetics/*metabolism ; Protein-Tyrosine Kinases/genetics/metabolism ; Spleen/immunology ; T-Lymphocytes/cytology/enzymology/immunology
    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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  • 2
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    Neuroscience: hidden female talent (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-05-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Jai Y -- Dickson, Barry J -- England -- Nature. 2008 May 1;453(7191):41-2. doi: 10.1038/453041a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451846" target="_blank"〉PubMed〈/a〉
    Keywords: *Animal Communication ; Animals ; Courtship ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/genetics/*physiology/radiation effects ; Female ; Male ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/metabolism/radiation effects ; Psychomotor Performance/physiology/radiation effects ; *Sex Characteristics ; Transcription Factors/genetics/metabolism ; Vibration ; Wings, Animal/physiology/radiation effects
    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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  • 3
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    Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-06-11
    Description: The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195509/" 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/PMC3195509/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Yonghao -- Yoon, Sang-Oh -- Poulogiannis, George -- Yang, Qian -- Ma, Xiaoju Max -- Villen, Judit -- Kubica, Neil -- Hoffman, Gregory R -- Cantley, Lewis C -- Gygi, Steven P -- Blenis, John -- CA46595/CA/NCI NIH HHS/ -- GM051405/GM/NIGMS NIH HHS/ -- HG3456/HG/NHGRI NIH HHS/ -- R00 CA140789/CA/NCI NIH HHS/ -- R00 CA140789-04/CA/NCI NIH HHS/ -- R00CA140789/CA/NCI NIH HHS/ -- R01 GM041890/GM/NIGMS NIH HHS/ -- R01 GM051405/GM/NIGMS NIH HHS/ -- R01 GM051405-14/GM/NIGMS NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- R01 HG003456/HG/NHGRI NIH HHS/ -- R01 HG003456-07/HG/NHGRI NIH HHS/ -- R37 CA046595/CA/NCI NIH HHS/ -- R37 CA046595-22/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2011 Jun 10;332(6035):1322-6. doi: 10.1126/science.1199484.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21659605" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibiotics, Antineoplastic/pharmacology ; Cell Line ; GRB10 Adaptor Protein/*metabolism ; Humans ; Insulin/*metabolism ; Mice ; Molecular Sequence Data ; Multiprotein Complexes ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Proteins/*metabolism ; Proteome/metabolism ; *Signal Transduction/drug effects ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases
    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
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    Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-10-18
    Description: Human immunodeficiency virus-1 (HIV-1) Vif is essential for viral evasion of host antiviral factor CEM15/APOBEC3G. We report that Vif interacts with cellular proteins Cul5, elongins B and C, and Rbx1 to form an Skp1-cullin-F-box (SCF)-like complex. The ability of Vif to suppress antiviral activity of APOBEC3G was specifically dependent on Cul5-SCF function, allowing Vif to interact with APOBEC3G and induce its ubiquitination and degradation. A Vif mutant that interacted with APOBEC3G but not with Cul5-SCF was functionally inactive. The Cul5-SCF was also required for Vif function in distantly related simian immunodeficiency virus mac. These results indicate that the conserved Cul5-SCF pathway used by Vif is a potential target for antiviral development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Xianghui -- Yu, Yunkai -- Liu, Bindong -- Luo, Kun -- Kong, Wei -- Mao, Panyong -- Yu, Xiao-Fang -- 1S10-RR14702/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2003 Nov 7;302(5647):1056-60. Epub 2003 Oct 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14564014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carrier Proteins/genetics/metabolism ; Cell Line ; Cullin Proteins/genetics/*metabolism ; Cytidine Deaminase ; Gene Products, vif/genetics/*metabolism ; HIV-1/genetics/*physiology ; Humans ; Mutation ; Nucleoside Deaminases ; Proteins/*metabolism ; Repressor Proteins ; Transcription Factors/genetics/metabolism ; Transfection ; Ubiquitin/*metabolism ; Virus Replication ; vif Gene Products, Human Immunodeficiency Virus
    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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  • 5
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    A draft sequence for the genome of the domesticated silkworm (Bombyx mori) (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2004-12-14
    Description: We report a draft sequence for the genome of the domesticated silkworm (Bombyx mori), covering 90.9% of all known silkworm genes. Our estimated gene count is 18,510, which exceeds the 13,379 genes reported for Drosophila melanogaster. Comparative analyses to fruitfly, mosquito, spider, and butterfly reveal both similarities and differences in gene content.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xia, Qingyou -- Zhou, Zeyang -- Lu, Cheng -- Cheng, Daojun -- Dai, Fangyin -- Li, Bin -- Zhao, Ping -- Zha, Xingfu -- Cheng, Tingcai -- Chai, Chunli -- Pan, Guoqing -- Xu, Jinshan -- Liu, Chun -- Lin, Ying -- Qian, Jifeng -- Hou, Yong -- Wu, Zhengli -- Li, Guanrong -- Pan, Minhui -- Li, Chunfeng -- Shen, Yihong -- Lan, Xiqian -- Yuan, Lianwei -- Li, Tian -- Xu, Hanfu -- Yang, Guangwei -- Wan, Yongji -- Zhu, Yong -- Yu, Maode -- Shen, Weide -- Wu, Dayang -- Xiang, Zhonghuai -- Yu, Jun -- Wang, Jun -- Li, Ruiqiang -- Shi, Jianping -- Li, Heng -- Li, Guangyuan -- Su, Jianning -- Wang, Xiaoling -- Li, Guoqing -- Zhang, Zengjin -- Wu, Qingfa -- Li, Jun -- Zhang, Qingpeng -- Wei, Ning -- Xu, Jianzhe -- Sun, Haibo -- Dong, Le -- Liu, Dongyuan -- Zhao, Shengli -- Zhao, Xiaolan -- Meng, Qingshun -- Lan, Fengdi -- Huang, Xiangang -- Li, Yuanzhe -- Fang, Lin -- Li, Changfeng -- Li, Dawei -- Sun, Yongqiao -- Zhang, Zhenpeng -- Yang, Zheng -- Huang, Yanqing -- Xi, Yan -- Qi, Qiuhui -- He, Dandan -- Huang, Haiyan -- Zhang, Xiaowei -- Wang, Zhiqiang -- Li, Wenjie -- Cao, Yuzhu -- Yu, Yingpu -- Yu, Hong -- Li, Jinhong -- Ye, Jiehua -- Chen, Huan -- Zhou, Yan -- Liu, Bin -- Wang, Jing -- Ye, Jia -- Ji, Hai -- Li, Shengting -- Ni, Peixiang -- Zhang, Jianguo -- Zhang, Yong -- Zheng, Hongkun -- Mao, Bingyu -- Wang, Wen -- Ye, Chen -- Li, Songgang -- Wang, Jian -- Wong, Gane Ka-Shu -- Yang, Huanming -- Biology Analysis Group -- 1 P50 HG02351/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2004 Dec 10;306(5703):1937-40.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Southwest Agricultural University, Chongqing Beibei, 400716, China. xiaqy@swau.cq.cn〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15591204" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Animals ; Anopheles/genetics ; Body Patterning/genetics ; Bombyx/*genetics/growth & development/metabolism ; Butterflies/genetics ; Computational Biology ; DNA Transposable Elements ; Drosophila melanogaster/genetics ; Exocrine Glands/metabolism ; Expressed Sequence Tags ; Female ; Genes, Homeobox ; *Genes, Insect ; *Genome ; Immunity, Innate/genetics ; Insect Hormones/genetics ; Insect Proteins/genetics ; Male ; Molecular Sequence Data ; *Sequence Analysis, DNA ; Sequence Homology, Nucleic Acid ; Sex Determination Processes ; Spiders/genetics ; Wings, Animal/growth & development
    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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    Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-05
    Description: Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of beta-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601659/" 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/PMC3601659/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grivennikov, Sergei I -- Wang, Kepeng -- Mucida, Daniel -- Stewart, C Andrew -- Schnabl, Bernd -- Jauch, Dominik -- Taniguchi, Koji -- Yu, Guann-Yi -- Osterreicher, Christoph H -- Hung, Kenneth E -- Datz, Christian -- Feng, Ying -- Fearon, Eric R -- Oukka, Mohamed -- Tessarollo, Lino -- Coppola, Vincenzo -- Yarovinsky, Felix -- Cheroutre, Hilde -- Eckmann, Lars -- Trinchieri, Giorgio -- Karin, Michael -- AI043477/AI/NIAID NIH HHS/ -- DK035108/DK/NIDDK NIH HHS/ -- DK080506/DK/NIDDK NIH HHS/ -- K08 DK081830/DK/NIDDK NIH HHS/ -- K99 DK088589/DK/NIDDK NIH HHS/ -- K99-DK088589/DK/NIDDK NIH HHS/ -- R01 AA020703/AA/NIAAA NIH HHS/ -- R01 AI043477/AI/NIAID NIH HHS/ -- R01 AI050265/AI/NIAID NIH HHS/ -- R01 CA082223/CA/NCI NIH HHS/ -- R01CA082223/CA/NCI NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):254-8. doi: 10.1038/nature11465.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23034650" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoma/genetics/immunology/*microbiology/*pathology ; Animals ; Bacteria/metabolism/pathogenicity ; Cell Division ; Cell Transformation, Neoplastic/*pathology ; Colitis/complications ; Colorectal Neoplasms/genetics/immunology/*microbiology/*pathology ; Disease Models, Animal ; Disease-Free Survival ; Genes, APC ; Humans ; Inflammation/genetics/immunology/microbiology/pathology ; Interleukin-17/genetics/*immunology ; Interleukin-23/deficiency/genetics/*immunology ; Mice ; Mice, Inbred C57BL ; Myeloid Cells/immunology/metabolism ; Myeloid Differentiation Factor 88/immunology/metabolism ; Signal Transduction ; Toll-Like Receptors/immunology/metabolism ; Tumor Microenvironment ; beta Catenin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Dopamine neurons modulate pheromone responses in Drosophila courtship learning (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-08-21
    Description: Learning through trial-and-error interactions allows animals to adapt innate behavioural 'rules of thumb' to the local environment, improving their prospects for survival and reproduction. Naive Drosophila melanogaster males, for example, court both virgin and mated females, but learn through experience to selectively suppress futile courtship towards females that have already mated. Here we show that courtship learning reflects an enhanced response to the male pheromone cis-vaccenyl acetate (cVA), which is deposited on females during mating and thus distinguishes mated females from virgins. Dissociation experiments suggest a simple learning rule in which unsuccessful courtship enhances sensitivity to cVA. The learning experience can be mimicked by artificial activation of dopaminergic neurons, and we identify a specific class of dopaminergic neuron that is critical for courtship learning. These neurons provide input to the mushroom body (MB) gamma lobe, and the DopR1 dopamine receptor is required in MBgamma neurons for both natural and artificial courtship learning. Our work thus reveals critical behavioural, cellular and molecular components of the learning rule by which Drosophila adjusts its innate mating strategy according to experience.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keleman, Krystyna -- Vrontou, Eleftheria -- Kruttner, Sebastian -- Yu, Jai Y -- Kurtovic-Kozaric, Amina -- Dickson, Barry J -- England -- Nature. 2012 Sep 6;489(7414):145-9. doi: 10.1038/nature11345.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr Bohrgasse 7, A-1030 Vienna, Austria. keleman@imp.ac.at〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22902500" target="_blank"〉PubMed〈/a〉
    Keywords: Acetates/analysis/pharmacology ; Animals ; Brain/cytology/drug effects ; *Courtship ; Dopamine/*metabolism ; Dopaminergic Neurons/drug effects/*metabolism ; Drosophila melanogaster/cytology/*drug effects/*physiology ; Female ; Learning/drug effects/*physiology ; Male ; Mushroom Bodies/cytology/drug effects/physiology ; Oleic Acids/analysis/pharmacology ; Pheromones/analysis/pharmacology ; Presynaptic Terminals/drug effects/physiology ; Receptors, Dopamine/genetics/metabolism ; Sex Attractants/analysis/*pharmacology ; Sexual Behavior, Animal/*drug effects/physiology ; Synaptic Transmission/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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  • 8
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    Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-30
    Description: Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of 〉90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648562/" 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/PMC4648562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lawson, Devon A -- Bhakta, Nirav R -- Kessenbrock, Kai -- Prummel, Karin D -- Yu, Ying -- Takai, Ken -- Zhou, Alicia -- Eyob, Henok -- Balakrishnan, Sanjeev -- Wang, Chih-Yang -- Yaswen, Paul -- Goga, Andrei -- Werb, Zena -- CA136717/CA/NCI NIH HHS/ -- CA180039/CA/NCI NIH HHS/ -- K23 HL116657/HL/NHLBI NIH HHS/ -- R01 CA136717/CA/NCI NIH HHS/ -- R01 CA180039/CA/NCI NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):131-5. doi: 10.1038/nature15260. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomy, University of California, San Francisco, California 94143, USA. ; Department of Medicine, University of California, San Francisco, California 94143, USA. ; Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, USA. ; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. ; Department of Cell and Molecular Biology, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416748" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/drug therapy/genetics/*pathology ; Cell Cycle/drug effects ; Cell Differentiation/drug effects/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Separation ; Cell Transformation, Neoplastic/drug effects/pathology ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Disease Models, Animal ; *Disease Progression ; Epithelial Cells/drug effects/pathology ; Epithelial-Mesenchymal Transition/genetics ; Flow Cytometry ; Gene Expression Profiling ; Genes, myc/genetics ; Humans ; Mesoderm/metabolism/pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Metastasis/drug therapy/*pathology ; Neoplastic Stem Cells/drug effects/metabolism/*pathology ; *Single-Cell Analysis ; Xenograft Model Antitumor Assays
    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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    Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-07-19
    Description: The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896866/" 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/PMC3896866/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venkatraman, Aparna -- He, Xi C -- Thorvaldsen, Joanne L -- Sugimura, Ryohichi -- Perry, John M -- Tao, Fang -- Zhao, Meng -- Christenson, Matthew K -- Sanchez, Rebeca -- Yu, Jaclyn Y -- Peng, Lai -- Haug, Jeffrey S -- Paulson, Ariel -- Li, Hua -- Zhong, Xiao-bo -- Clemens, Thomas L -- Bartolomei, Marisa S -- Li, Linheng -- GM51279/GM/NIGMS NIH HHS/ -- R01 GM087376/GM/NIGMS NIH HHS/ -- R37 GM051279/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Aug 15;500(7462):345-9. doi: 10.1038/nature12303. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863936" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/*cytology/*physiology ; Animals ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Developmental ; *Genomic Imprinting ; Insulin-Like Growth Factor II/*genetics/*metabolism ; Mice ; RNA, Long Noncoding/*genetics/*metabolism ; Receptor, IGF Type 1/genetics ; Signal Transduction ; Transcriptional Activation
    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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    PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-01-04
    Description: Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, has long been postulated as a cellular correlate of learning and memory. Although LTP can persist for long periods of time, the mechanisms underlying LTP maintenance, in the midst of ongoing protein turnover and synaptic activity, remain elusive. Sustained activation of the brain-specific protein kinase C (PKC) isoform protein kinase M-zeta (PKM-zeta) has been reported to be necessary for both LTP maintenance and long-term memory. Inhibiting PKM-zeta activity using a synthetic zeta inhibitory peptide (ZIP) based on the PKC-zeta pseudosubstrate sequence reverses established LTP in vitro and in vivo. More notably, infusion of ZIP eliminates memories for a growing list of experience-dependent behaviours, including active place avoidance, conditioned taste aversion, fear conditioning and spatial learning. However, most of the evidence supporting a role for PKM-zeta in LTP and memory relies heavily on pharmacological inhibition of PKM-zeta by ZIP. To further investigate the involvement of PKM-zeta in the maintenance of LTP and memory, we generated transgenic mice lacking PKC-zeta and PKM-zeta. We find that both conventional and conditional PKC-zeta/PKM-zeta knockout mice show normal synaptic transmission and LTP at Schaffer collateral-CA1 synapses, and have no deficits in several hippocampal-dependent learning and memory tasks. Notably, ZIP still reverses LTP in PKC-zeta/PKM-zeta knockout mice, indicating that the effects of ZIP are independent of PKM-zeta.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830948/" 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/PMC3830948/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Volk, Lenora J -- Bachman, Julia L -- Johnson, Richard -- Yu, Yilin -- Huganir, Richard L -- NS36715/NS/NINDS NIH HHS/ -- P30 NS050274/NS/NINDS NIH HHS/ -- R01 NS036715/NS/NINDS NIH HHS/ -- T32 EY017203/EY/NEI NIH HHS/ -- T32 MH015330/MH/NIMH NIH HHS/ -- T32MH15330/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 17;493(7432):420-3. doi: 10.1038/nature11802. Epub 2013 Jan 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23283174" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Avoidance Learning/drug effects/physiology ; Behavior, Animal/drug effects/physiology ; Conditioning, Classical ; Fear ; Female ; Hippocampus/drug effects/*physiology ; Isoenzymes/deficiency/genetics/metabolism ; Lipopeptides/pharmacology ; Long-Term Potentiation/drug effects/genetics/physiology ; Male ; Memory, Long-Term/drug effects/*physiology ; Mice ; Mice, Knockout ; Neuronal Plasticity/genetics/*physiology ; Protein Kinase C/antagonists & inhibitors/deficiency/genetics/*metabolism ; Synapses/drug effects/*metabolism ; Synaptic Transmission/drug effects
    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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