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Transcriptional regulation by CtBP is mediated by HDAC- and HAT-complex recruitment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-94058OAI: oai:DiVA.org:uu-94058DiVA: diva2:167772
Available from: 2006-03-09 Created: 2006-03-09 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Modulation of Adenovirus E1A Activities by the Cellular Corepressor CtBP
Open this publication in new window or tab >>Modulation of Adenovirus E1A Activities by the Cellular Corepressor CtBP
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adenovirus E1A is needed to activate early viral genes and induce cell cycle progression to optimise the conditions for viral replication. This is mostly achieved through interactions between the first exon of E1A and cellular transcriptional regulatory proteins. The carboxy terminus of E1A binds the cellular corepressor of transcription C-terminal Binding Protein (CtBP), resulting in derepression of CtBP target genes.

Inducible stable U2OS cell lines were established, expressing wild type E1A (E1Awt) and a mutant unable to bind CtBP (E1A∆CID). Low inducible levels and loss of protein expression after prolonged induction together with induction of apoptosis were consistent with the fact that wild type E1A is a cytotoxic protein and correlated with the ability of CtBP to repress proapoptotic genes. E1A∆CID did not induce apoptosis and could be expressed at high levels for prolonged time periods. Moreover, the binding of CtBP contributed to E1A-induced activation of viral E1B and E4 genes, through possible targeting of Sp1 and ATF transcription factors.

In a micorarray study on mRNA levels in E1A-expressing cells, several genes consistent with the tumour suppressive and apoptotic properties of E1Awt were identified as differentially expressed. Furthermore, the differences between the two cell lines correlated with the presence of binding sites for CtBP-interacting transcription factors in the promoters of regulated genes, enabling the possible identification of new CtBP target genes.

Finally, a molecular characterisation of the CtBP mechanism of repression revealed that positioning proximal to the basal promoter element was required for efficient repression, suggesting that CtBP interferes with the basal transcriptional machinery. Two separate domains were identified in CtBP, conferring transcriptional repression and activation when expressed alone, achieved through their interaction with HDACs and HATs, respectively. However, together they cooperate to ensure maximal repression through recruitment of histone deacetylase and inhibition of histone acetyl transferase activity.

Together, these data shows important modulation of E1A activities by the binding of CtBP and suggests the involvement of acetylation/deacetylation complexes for the regulation of E1A function.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 111
Cell and molecular biology, Adenovirus, E1A, CtBP, transcription regulation, TetON, microarray, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-6485 (URN)91-554-6474-2 (ISBN)
Public defence
2006-03-30, C10:301, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-03-09 Created: 2006-03-09Bibliographically approved

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Svensson, Catharina
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