The study of the nuclear replicating, double stranded DNA viruses (herpes, adeno and papova viruses) has yielded much information regarding the molecular biology of gene expression of both viruses and eucaryotes in general. We have extended these studies through the examination of several aspects of gene expression control of the late genes of the papova virus, Simian virus 40 (SV40). Specifically: 1. We have examined the mechanisms by which the SV40 early gene product, large T antigen, trans- activates the promoter for late gene expression, and we have defined elements within the late promoter which respond to trans- activation. Our data suggest that T antigen mediates the activation of the late promoter (and cellular promoters) indirectly through the utilization of a cellular trans-acting factor(s). Such abrogation of cellular trans-acting cellular phenotypic changes associated with viral disease and transformation. We propose to use several lines of investigation to further analyze the trans- activation mechanism and exactly delineate the elements of the late promoter. In addition, we will initiate experiments to identify cellular trans-acting factors which direct late promoter activation. 2. We have defined sequences of the 3'-slide of the hexanucleotide AAUAAA which effect efficiency of polyadenylation of the viral late RNAs. Our data indicate that there may be separable parts to this downstream signal element. We propose to carefully define these elements and their interrelatedness. Additionally, our data suggests that sequences on the 5'-side of the late AAUAAA affect the level of late transcripts, possibly by stabilizing the transcript. We propose to examine these sequences and determine their function. 3. We have examined the effect of the SV40 agnoprotein on the expression and intracellular localization of late viral gene products. We propose to continue these studies in order to better understand the phenomenon and determine the function(s) of the agnoprotein.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028379-09
Application #
3168112
Study Section
Virology Study Section (VR)
Project Start
1980-06-01
Project End
1991-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Clippinger, Amy J; Maguire, Tobi G; Alwine, James C (2011) The changing role of mTOR kinase in the maintenance of protein synthesis during human cytomegalovirus infection. J Virol 85:3930-9
Yu, Yongjun; Clippinger, Amy J; Pierciey Jr, Francis J et al. (2011) Viruses and metabolism: alterations of glucose and glutamine metabolism mediated by human cytomegalovirus. Adv Virus Res 80:49-67
Yu, Yongjun; Maguire, Tobi G; Alwine, James C (2011) Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection. J Virol 85:1573-80
Buchkovich, Nicholas J; Maguire, Tobi G; Alwine, James C (2010) Role of the endoplasmic reticulum chaperone BiP, SUN domain proteins, and dynein in altering nuclear morphology during human cytomegalovirus infection. J Virol 84:7005-17
Chambers, Jeremy W; Maguire, Tobi G; Alwine, James C (2010) Glutamine metabolism is essential for human cytomegalovirus infection. J Virol 84:1867-73
Buchkovich, Nicholas J; Yu, Yongjun; Pierciey Jr, Francis J et al. (2010) Human cytomegalovirus induces the endoplasmic reticulum chaperone BiP through increased transcription and activation of translation by using the BiP internal ribosome entry site. J Virol 84:11479-86
Buchkovich, Nicholas J; Maguire, Tobi G; Paton, Adrienne W et al. (2009) The endoplasmic reticulum chaperone BiP/GRP78 is important in the structure and function of the human cytomegalovirus assembly compartment. J Virol 83:11421-8
Yu, Yongjun; Alwine, James C (2008) Interaction between simian virus 40 large T antigen and insulin receptor substrate 1 is disrupted by the K1 mutation, resulting in the loss of large T antigen-mediated phosphorylation of Akt. J Virol 82:4521-6
Alwine, J C (2008) Modulation of host cell stress responses by human cytomegalovirus. Curr Top Microbiol Immunol 325:263-79
Buchkovich, Nicholas J; Yu, Yongjun; Zampieri, Carisa A et al. (2008) The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway. Nat Rev Microbiol 6:266-75

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