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Effects of polyomavirus T antigens on cellular signal transduction pathways
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The early viral proteins, the tumor (T) antigens, of mouse polyomavirus,stimulate cell growth by interaction with cellular growth regulating proteins.The viral interference with cellular growth regulation may, eventually, alsoresult in effects on cellular apoptosis (programmed cell death) mechanisms.The aim of this work has been to contribute to the understanding ofpolyomavirus T antigens effect on cellular growth regulation and apoptosis.

Large T antigen stimulates host cell DNA synthesis, and it has theability to immortalize primary cells. it is also required for initiation of viralDNA replication, and regulation of viral transcription. We found that mutantlarge T antigens, with deletions in the conserved retinoblastoma proteinbinding-site, had defects in the immortalizing activity. Furthermore, themutants could no longer stimulate viral DNA replication in slowly growingcells. Thus, Rb-binding by large T antigen is probably important for viralreplication in quiescent cells.

Middle T antigen is the main transforming protein of polyomavirus. Itinteracts with a number of cellular proteins, involved in signal transduction.In this work we demonstrate that middle T antigen induces sensitivity to TNF-α- and H2O2- induced apoptosis. This induced sensitivit is dependent on the ability of middle T antigen to interact with the cellular proteinsphosphatidylinositol 3-kinase and Shc.

Small T antigen stimulate viral DNA synthesis, and cooperates withmiddle T antigen in transformation. We show here, that small T antigen alsohas a protective effect against cytotoxicity induced by TNF-α and H2O2.Furthermore, we demonstrate two possible mechanisms for the anti-apoptoticeffect, induction of NF-κB activity and increased expression of heat shockprotein 27.

The protective effect of small T antigen appears to be important forpolyomavirus induced tumor formation. Middle T antigen expression has anegative effect on the development of tumors by FM3A cells in mice.However, expression of small T antigen overcame this negative effect, leading to increased tumor formation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , 47 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 744
Keyword [en]
Keyword [sv]
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Virology
URN: urn:nbn:se:uu:diva-1224ISBN: 91-554-4156-4OAI: oai:DiVA.org:uu-1224DiVA: diva2:160782
Public defence
1998-03-25, lecture hall B10 at the Biomedical Centre, Uppsala, Uppsala, 09:15
Available from: 1998-03-04 Created: 1998-03-04Bibliographically approved

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