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  1. Article ; Online: Aging with ING: a comparative study of different forms of stress induced premature senescence.

    Rajarajacholan, Uma Karthika / Riabowol, Karl

    Oncotarget

    2015  Volume 6, Issue 33, Page(s) 34118–34127

    Abstract: Cell senescence contributes to organismal aging and is induced by telomere erosion and an ensuing DNA damage signal as cells reach the end of their replicative lifespan in vitro or in vivo. Stresses induced by oncogene or tumor suppressor hyperactivation, ...

    Abstract Cell senescence contributes to organismal aging and is induced by telomere erosion and an ensuing DNA damage signal as cells reach the end of their replicative lifespan in vitro or in vivo. Stresses induced by oncogene or tumor suppressor hyperactivation, oxidative stress, ionizing radiation and other DNA damaging agents result in forms of stress induced premature senescence (SIPS) that show similarities to replicative senescence. Since replicative senescence and SIPS occur over many days and many population doublings of the mass cultures of primary cells used to study senescence, the sequence of events that occur downstream of senescence signaling can be challenging to define. Here we compare a new model of ING1a-induced senescence with several other forms of senescence. The ING1a epigenetic regulator synchronously induces senescence in mass cultures several-fold faster than all other agents, taking 24 and 36 hours to activate the Rb/ p16INK4a, but not the p53 tumor suppressor axis to efficiently induce senescence. ING1a induces expression of intersectin 2, a scaffold protein necessary for endocytosis, altering the stoichiometry of endocytosis proteins, subsequently blocking growth factor uptake leading to activation of Rb signaling to block cell growth. ING1a acts as a novel link in the activation of the Rb pathway that can impose senescence in the absence of activating p53-mediated DNA damage signaling, and should prove useful in defining the molecular events contributing to Rb-induced senescence.
    MeSH term(s) Actin Cytoskeleton/metabolism ; Adaptor Proteins, Vesicular Transport/biosynthesis ; Aging, Premature/genetics ; Cell Line ; Cellular Senescence/genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage/genetics ; Endocytosis/physiology ; Endothelial Cells/metabolism ; Humans ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins/genetics ; Keratinocytes/metabolism ; Nuclear Proteins/genetics ; Retinoblastoma Protein/metabolism ; Stress, Physiological/genetics ; Telomere Homeostasis/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/genetics
    Chemical Substances Adaptor Proteins, Vesicular Transport ; Cyclin-Dependent Kinase Inhibitor p16 ; Cyclin-Dependent Kinase Inhibitor p21 ; ING1 protein, human ; ITSN2 protein, human ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins ; Nuclear Proteins ; Retinoblastoma Protein ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins
    Language English
    Publishing date 2015-10-27
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.5947
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ING1 regulates rRNA levels by altering nucleolar chromatin structure and mTOR localization.

    Rajarajacholan, Uma Karthika / Thalappilly, Subhash / Riabowol, Karl

    Nucleic acids research

    2016  Volume 45, Issue 4, Page(s) 1776–1792

    Abstract: Epigenetic, transcriptional and signaling processes in the nucleolus regulate rRNA transcription and cell growth. We report here that the tumor suppressor ING1b binds rDNA, regulates rDNA chromatin modifications and affects nucleolar localization of mTOR ...

    Abstract Epigenetic, transcriptional and signaling processes in the nucleolus regulate rRNA transcription and cell growth. We report here that the tumor suppressor ING1b binds rDNA, regulates rDNA chromatin modifications and affects nucleolar localization of mTOR to modulate rRNA levels. ING1 represses rDNA transcription by recruiting HDAC1 to rDNA loci, increasing its association with the NoRC complex and deacetylating the histone H3K9 and H3K27 marks of active transcription. Loss of ING1 enhances nucleolar localization of phospho-mTOR and its association with Raptor and GβL, even during rapamycin treatment. ING1 inhibits rDNA transcription by inhibiting UBF activity and its interaction with mTOR. Regulation of rDNA heterochromatin and rRNA synthesis by ING1 is also apparent during normal cell growth and during cell stress. Moreover, this function was also important during PMA induced differentiation of THP1 cells, since knocking down ING1 affected the process by inhibiting rRNA transcriptional repression. These observations show that ING1 regulates the nucleolar epigenome and rDNA transcription suggesting that regulation of protein synthesis might serve as the basis for ING1 function as a type II tumor suppressor.
    MeSH term(s) Cell Differentiation/genetics ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; Epigenesis, Genetic ; Gene Expression Regulation ; Gene Silencing ; Genes, Tumor Suppressor ; Glucose/metabolism ; Histone Deacetylase 1/metabolism ; Humans ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins/metabolism ; Monocytes/cytology ; Monocytes/metabolism ; Multiprotein Complexes/metabolism ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Transport ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA, Ribosomal/genetics ; TOR Serine-Threonine Kinases/metabolism ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Chromatin ; ING1 protein, human ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins ; Multiprotein Complexes ; Nuclear Proteins ; RNA Precursors ; RNA, Ribosomal ; Tumor Suppressor Proteins ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Histone Deacetylase 1 (EC 3.5.1.98) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2016-11-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkw1161
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  3. Article ; Online: The ING1a tumor suppressor regulates endocytosis to induce cellular senescence via the Rb-E2F pathway.

    Uma Karthika Rajarajacholan / Subhash Thalappilly / Karl Riabowol

    PLoS Biology, Vol 11, Iss 3, p e

    2013  Volume 1001502

    Abstract: The INhibitor of Growth (ING) proteins act as type II tumor suppressors and epigenetic regulators, being stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the alternatively spliced ING1a tumor suppressor ...

    Abstract The INhibitor of Growth (ING) proteins act as type II tumor suppressors and epigenetic regulators, being stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the alternatively spliced ING1a tumor suppressor increases >10-fold during replicative senescence. ING1a overexpression inhibits growth; induces a large flattened cell morphology and the expression of senescence-associated β-galactosidase; increases Rb, p16, and cyclin D1 levels; and results in the accumulation of senescence-associated heterochromatic foci. Here we identify ING1a-regulated genes and find that ING1a induces the expression of a disproportionate number of genes whose products encode proteins involved in endocytosis. Intersectin 2 (ITSN2) is most affected by ING1a, being rapidly induced >25-fold. Overexpression of ITSN2 independently induces expression of the p16 and p57(KIP2) cyclin-dependent kinase inhibitors, which act to block Rb inactivation, acting as downstream effectors of ING1a. ITSN2 is also induced in normally senescing cells, consistent with elevated levels of ING1a inducing ITSN2 as part of a normal senescence program. Inhibition of endocytosis or altering the stoichiometry of endosome components such as Rab family members similarly induces senescence. Knockdown of ITSN2 also blocks the ability of ING1a to induce a senescent phenotype, confirming that ITSN2 is a major transducer of ING1a-induced senescence signaling. These data identify a pathway by which ING1a induces senescence and indicate that altered endocytosis activates the Rb pathway, subsequently effecting a senescent phenotype.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The ING1a tumor suppressor regulates endocytosis to induce cellular senescence via the Rb-E2F pathway.

    Rajarajacholan, Uma Karthika / Thalappilly, Subhash / Riabowol, Karl

    PLoS biology

    2013  Volume 11, Issue 3, Page(s) e1001502

    Abstract: The INhibitor of Growth (ING) proteins act as type II tumor suppressors and epigenetic regulators, being stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the alternatively spliced ING1a tumor suppressor ...

    Abstract The INhibitor of Growth (ING) proteins act as type II tumor suppressors and epigenetic regulators, being stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the alternatively spliced ING1a tumor suppressor increases >10-fold during replicative senescence. ING1a overexpression inhibits growth; induces a large flattened cell morphology and the expression of senescence-associated β-galactosidase; increases Rb, p16, and cyclin D1 levels; and results in the accumulation of senescence-associated heterochromatic foci. Here we identify ING1a-regulated genes and find that ING1a induces the expression of a disproportionate number of genes whose products encode proteins involved in endocytosis. Intersectin 2 (ITSN2) is most affected by ING1a, being rapidly induced >25-fold. Overexpression of ITSN2 independently induces expression of the p16 and p57(KIP2) cyclin-dependent kinase inhibitors, which act to block Rb inactivation, acting as downstream effectors of ING1a. ITSN2 is also induced in normally senescing cells, consistent with elevated levels of ING1a inducing ITSN2 as part of a normal senescence program. Inhibition of endocytosis or altering the stoichiometry of endosome components such as Rab family members similarly induces senescence. Knockdown of ITSN2 also blocks the ability of ING1a to induce a senescent phenotype, confirming that ITSN2 is a major transducer of ING1a-induced senescence signaling. These data identify a pathway by which ING1a induces senescence and indicate that altered endocytosis activates the Rb pathway, subsequently effecting a senescent phenotype.
    MeSH term(s) Adaptor Proteins, Vesicular Transport/genetics ; Adaptor Proteins, Vesicular Transport/metabolism ; Cell Line ; Cellular Senescence/genetics ; Cellular Senescence/physiology ; E2F Transcription Factors/genetics ; E2F Transcription Factors/metabolism ; Endocytosis/genetics ; Endocytosis/physiology ; Humans ; Immunoblotting ; Immunoprecipitation ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Real-Time Polymerase Chain Reaction ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; beta-Galactosidase/genetics ; beta-Galactosidase/metabolism
    Chemical Substances Adaptor Proteins, Vesicular Transport ; E2F Transcription Factors ; ING1 protein, human ; ITSN2 protein, human ; Inhibitor of Growth Protein 1 ; Intracellular Signaling Peptides and Proteins ; Nuclear Proteins ; Retinoblastoma Protein ; Tumor Suppressor Proteins ; beta-Galactosidase (EC 3.2.1.23)
    Language English
    Publishing date 2013-03-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126776-5
    ISSN 1545-7885 ; 1544-9173
    ISSN (online) 1545-7885
    ISSN 1544-9173
    DOI 10.1371/journal.pbio.1001502
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6193: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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