Effects of polyomavirus T antigens on cellular signal transduction pathways

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

Nyckelord

Biochemistry

Biokemi

Biochemistry

Biokemi

Medical Virology

medicinsk virologi

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