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The Interaction of the Adenovirus E1B-55K Protein with a Histone Deacetylase Complex: Its Importance in Regulation of P53 Protein Functions
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human tumour suppressor protein p53 is an effective inhibitor of cell growth, by inducing cell cycle arrest and apoptosis. However, p53-induced cell growth inhibition can be detrimental for virus multiplication. Therefore, viruses encode for proteins, which can interfere with the functions of the p53 protein. Human adenoviruses encode for a transcription repressor protein named E1B-55K, which inhibits the activity of the p53 protein during a lytic adenovirus infection.

In this thesis, we have studied the biochemical characteristics of the E1B-55K protein and how the E1B-55K protein interferes with the function of p53 as a transcription factor.

Our data show that the E1B-55K protein interacts with the Sin3 co-repressor complex in adenovirus transformed and in adenovirus infected cells. Furthermore, the E1B-55K protein recruites a histone deacetylase activity, indicating that the E1B-55K protein is associated with a functional chromatin modifying complex. We also show that in addition to repressing p53-activated transcription, E1B-55K could also relieve p53-mediated repression of the survivin and Map4 promoters.

Previous results have shown that E1B-55K inhibits p53 as a transcriptional activator of the p21/CDKN1A promoter. Here we show that the E1B-55K protein prevents p53 from inducing histone H3 and H4 acetylation on p21/CDKN1A promoter, which coincided with the inhibition of p21/CDKN1A protein expression. Notably, the Sin3 complex was detected in the vicinity of the p53 binding site on the p21/CDKN1A promoter, suggesting that the E1B-55K protein blocked p53-mediated histone acetylation by recruitment of a histone deacetylase activity. Inhibition of p21/CDKN1A protein expression might be the reason, why the E1B-55K protein alleviates p53-dependent transcriptional repression of the survivin promoter.

Finally, we show that oligomerisation of the E1B-55K protein is important for the defined subcellular localization of the protein and for its function as a repressor of p53-activated transcription.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 62
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1314
Keywords [en]
Biochemistry, adenovirus, E1B-55K, p53, histone acetylation, Sin3
Keywords [sv]
Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-3887ISBN: 91-554-5829-7 (print)OAI: oai:DiVA.org:uu-3887DiVA, id: diva2:163819
Public defence
2004-01-30, C10-305, BMC, Husargatan3, BMC, 75123, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-12-22 Created: 2003-12-22Bibliographically approved
List of papers
1. The adenovirus-2 E1B-55K protein interacts with a mSin3A/histone deacetylase 1 complex.
Open this publication in new window or tab >>The adenovirus-2 E1B-55K protein interacts with a mSin3A/histone deacetylase 1 complex.
2000 (English)In: FEBS Letters, ISSN 0014-5793, Vol. 476, no 3, p. 248-252Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91174 (URN)
Available from: 2003-12-22 Created: 2003-12-22 Last updated: 2011-06-30Bibliographically approved
2. Adenovirus 2 E1B-55K protein relieves p53-mediated transcriptional repression of the survivin and MAP4 promoters.
Open this publication in new window or tab >>Adenovirus 2 E1B-55K protein relieves p53-mediated transcriptional repression of the survivin and MAP4 promoters.
2003 (English)In: FEBS Letters, ISSN 0014-5793, Vol. 552, no 2-3, p. 214-218Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91175 (URN)
Available from: 2003-12-22 Created: 2003-12-22 Last updated: 2011-06-30Bibliographically approved
3. The adenovirus E1B-55K protein inhibits p53 as a transcriptional regulator protein by blocking p53-mediated histone acetylation.
Open this publication in new window or tab >>The adenovirus E1B-55K protein inhibits p53 as a transcriptional regulator protein by blocking p53-mediated histone acetylation.
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91176 (URN)
Available from: 2003-12-22 Created: 2003-12-22 Last updated: 2011-06-30Bibliographically approved

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