Investigation of the role of ING1a in Cellular Senescence and ING1b in Ribosomal DNA transcription

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atmire.migration.oldid2901
dc.contributor.advisorRiabowol, Karl
dc.contributor.authorRajarajacholan, Uma Karthika
dc.date.accessioned2015-02-03T18:52:17Z
dc.date.available2015-08-03T07:01:05Z
dc.date.issued2015-02-03
dc.date.submitted2015en
dc.description.abstractThe INhibitor of Growth (ING) proteins are type II tumor suppressors that regulate epigenetic state and transcription by functioning as stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the ING1a isoform increases more than 10-fold during replicative senescence. ING1a overexpression itself induced all features of senescence examined. In this study we have identified and characterized a causal role for endocytosis and signal transduction in inducing senescence-associated phenotypes. ING1a regulated endocytosis through transcriptional activation of endocytic adaptor ITSN2. Inhibition of endocytosis altered growth factor signaling pathways leading to Rb-mediated inhibition of E2F activity, enforcing a senescence phenotype. Overexpression of ITSN2 itself induced senescence-associated characteristics in primary cells. The upstream causal role of endocytosis during senescence induction was further confirmed by ING1a-mediated increase in ITSN2 prior to the appearance of senescence markers and also by induction of senescence-associated phenotypes upon altering the stoichiometry of endocytosis regulators. ING1b isoform is well characterized in terms of regulation of cell growth and tumor suppression. Nucleolar localization of ING1b has been previously reported to be associated with stress-induced apoptosis. In this work we observe that ING1 regulates histone acetylation and the chromatin state of rDNA by recruiting HDAC1. ING1 also regulated recruitment of RNA Pol I- associated transcription factor UBF to rDNA, and affected levels of both rRNA and protein synthesis in cells. A role for ING1-mediated rRNA repression was also observed during PMA-induced differentiation of THP-1 cells. We observed that nucleolar localization of ING1 required its NTS motifs while recruitment of HDAC was dependent on the ING1 unique N-terminal region. Knock down of ING1 increased rRNA transcription and affected cellular proliferation during stress. This study identifies two novel mechanisms by which ING1 exerts its tumor suppressor function, by affecting mitogenic signaling pathways and regulating the major transcription process in cells, and confirms that epigenetic processes play an essential role in these process.en_US
dc.description.embargoterms6 monthsen_US
dc.identifier.citationRajarajacholan, U. K. (2015). Investigation of the role of ING1a in Cellular Senescence and ING1b in Ribosomal DNA transcription (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26664en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/26664
dc.identifier.urihttp://hdl.handle.net/11023/2075
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.facultyMedicine
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectBiology--Molecular
dc.subjectBiochemistry
dc.subject.classificationING1en_US
dc.subject.classificationSenescenceen_US
dc.subject.classificationRibosomal DNAen_US
dc.subject.classificationNucleolusen_US
dc.subject.classificationEndocytosisen_US
dc.subject.classificationEpigeneticsen_US
dc.subject.classificationGrowth factor signallingen_US
dc.subject.classificationChromatinen_US
dc.titleInvestigation of the role of ING1a in Cellular Senescence and ING1b in Ribosomal DNA transcription
dc.typedoctoral thesis
thesis.degree.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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