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Characterisation of Ctbp Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1089 _____________________________ _____________________________ Characterisation of CtBP A Co-Repressor of Transcription that Interacts with the Adenovirus E1A Protein BY ANDERS SUNDQVIST ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001 Dissertation for the Degree of Doctor of Philosophy, Faculty of Medicine, in Medical Virology presented at Uppsala University in 2001 ABSTRACT Sundqvist, A. 2001. Characterisation of CtBP. A Co-Repressor of Transcription that Interacts with the Adenovirus E1A Protein. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1089. 50 pp. Uppsala. ISBN 91-554-5144-6. In this study, adenovirus E1A has been used to target and analyse the transcriptional function of the cellular C-terminal Binding Protein (CtBP). Transcription is a complex biochemical process that represents a major regulatory step in gene expression. Formation of condensed chromatin by histone deacetylation and inhibition of efficient assembly of the transcription machinery are hallmarks of transcriptional repression. During a virus infection, an extensive modulation of the host cell gene expression in favour of viral gene expression can be observed. For example, the transcription regulatory E1A protein from adenovirus has been proven to be a valuable research-tool in characterising cellular proteins controlling eukaryotic gene expression. Expression of a CtBP-binding peptide, encoded by the second exon of E1A, de- repressed transcription from a broad range of promoters, suggesting that CtBP functioned as a repressor of transcription. Artificial promoter recruitment of CtBP, by using different Gal4- fusion proteins, confirmed that CtBP functioned as a repressor. Repression of transcription by Gal4E1A-recruited CtBP was efficiently prevented by a CtBP binding competent E1A peptide, indicating that E1A relieved CtBP mediated repression by displacing CtBP from the promoter. Furthermore, Gal4CtBP repressed both basal and activated transcription in a distance dependent manner, suggesting that CtBP might repress transcription by interfering with the assembly of the basal transcription machinery. Interestingly, CtBP was found to interact with histone deacetylase-1 (HDAC-1) both in vivo and in vitro and endogenous CtBP could also recruit histone deacetylase activity. This might indicate that histone deacetylation was involved in CtBP mediated repression. However, Gal4CtBP mediated repression was insensitive to inhibition of histone deacetylase activity, suggesting an alternative function of HDAC-binding in CtBP mediated repression. In conclusion, this work demonstrates that CtBP can act as a general repressor of activated and basal transcription. Furthermore, although CtBP was shown to recruit histone deacetylase activity the relevance of this binding remains unclear. Key words: CtBP, HDAC, adenovirus, E1A, gene expression, repression. Anders Sundqvist, Department of Medical Biochemistry and Microbiology, Biomedical Centre, Box 582, SE-751 23 Uppsala, Sweden © Anders Sundqvist 2001 ISSN 0282-7476 ISBN 91-554-5144-6 Printed in Sweden by Eklundshofs Grafiska AB, Uppsala 2001 This thesis is based on the following articles, which in the text are referred to by their roman numerals: 1) Anders Sundqvist, Kerstin Sollerbrant and Catharina Svensson. 1998. The carboxy-terminal region of adenovirus E1A activates transcription through targetting of a C-terminal binding protein-histone deacetylase complex. FEBS Lett. 429: 183-188. 2) Anders Sundqvist, Edyta Bajak, Sindhulakshmi D. Karup, Kerstin Sollerbrant and Catharina Svensson. 2001. Functional knock-out of the co- repressor CtBP by the second exon of adenovirus E1A relives repression of transcription. Exp Cell Res. 268(2): 284-293. 3) Anders Sundqvist and Catharina Svensson. 2001. Molecular characterisation of transcriptional co-repressor CtBP. Manuscript. Reprints were made with permission from the publishers: Elsevier Science B.V. and Academic Press. Back at the lab bench…at last! TABLE OF CONTENTS ABBREVIATIONS AND DEFINITIONS............................................................................................1 INTRODUCTION ..................................................................................................................................2 CHROMATIN ........................................................................................................................................2 Chromatin modifications ................................................................................................................3 Acetylation-deacetylation ..........................................................................................................4 Phosphorylation.........................................................................................................................5 Methylation................................................................................................................................5 Ubiquitylation............................................................................................................................5 The "histone code".....................................................................................................................5 Chromatin remode .....................................................................................................................7 TRANSCRIPTION ................................................................................................................................7 Promoter structure ..........................................................................................................................8 The basal transcription machinery ................................................................................................9 RNA polymerase II...................................................................................................................10 DNA sequence-specific transcription factors ..............................................................................10 Co-factors .......................................................................................................................................11 TAFs.........................................................................................................................................11 Mediator ..................................................................................................................................12 USA..........................................................................................................................................12 Co-activators and co-repressors..............................................................................................12 Elongation.......................................................................................................................................13 How transcription might be regulated.........................................................................................13 Regulation of transcription factor activity ..................................................................................17 Protein stability........................................................................................................................17 Cellular localisation ................................................................................................................18 DNA binding ............................................................................................................................18 Phosphorylation and dephosphorylation .................................................................................18 THE ADENOVIRUS MODEL SYSTEM ..........................................................................................19 Adenovirus .....................................................................................................................................19 The adenovirus life cycle .........................................................................................................19 Early region 1A..............................................................................................................................20 Activation of transcription by E1A ..........................................................................................21 Repression of transcription by E1A .........................................................................................23 The role of E1A in cellular transformation..............................................................................23 CTBP, A CELLULAR CO-REPRESSOR OF TRANSCRIPTION ................................................24 CtBP interacting proteins .............................................................................................................25 Mechanisms of CtBP mediated repression ..................................................................................26 The biological role of CtBP...........................................................................................................26 Additional characteristics of CtBP...............................................................................................27 PRESENT INVESTIGATION ............................................................................................................28 Paper I: The carboxy-terminal region of adenovirus E1A activates transcription
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