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

Rajarajacholan, Uma Karthika

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

atmire.migration.oldid	2901
dc.contributor.advisor	Riabowol, Karl
dc.contributor.author	Rajarajacholan, Uma Karthika
dc.date.accessioned	2015-02-03T18:52:17Z
dc.date.available	2015-08-03T07:01:05Z
dc.date.issued	2015-02-03
dc.date.submitted	2015	en
dc.description.abstract	The 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.embargoterms	6 months	en_US
dc.identifier.citation	Rajarajacholan, 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/26664	en_US
dc.identifier.doi	http://dx.doi.org/10.11575/PRISM/26664
dc.identifier.uri	http://hdl.handle.net/11023/2075
dc.language.iso	eng
dc.publisher.faculty	Graduate Studies
dc.publisher.faculty	Medicine
dc.publisher.institution	University of Calgary	en
dc.publisher.place	Calgary	en
dc.rights	University 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.subject	Biology--Cell
dc.subject	Biology--Molecular
dc.subject	Biochemistry
dc.subject.classification	ING1	en_US
dc.subject.classification	Senescence	en_US
dc.subject.classification	Ribosomal DNA	en_US
dc.subject.classification	Nucleolus	en_US
dc.subject.classification	Endocytosis	en_US
dc.subject.classification	Epigenetics	en_US
dc.subject.classification	Growth factor signalling	en_US
dc.subject.classification	Chromatin	en_US
dc.title	Investigation of the role of ING1a in Cellular Senescence and ING1b in Ribosomal DNA transcription
dc.type	doctoral thesis
thesis.degree.discipline	Biochemistry and Molecular Biology
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.item.requestcopy	true