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Comparative Analysis of Polyomavirus T Antigens In Cellular Transformation

Seneca, Nicole (2014) Comparative Analysis of Polyomavirus T Antigens In Cellular Transformation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Polyomaviruses can induce tumors in animals and transformation of cells in culture by expression of the viral T antigen proteins. The most widely studied polyomavirus, SV40, expresses the large T antigen protein (LT), which interacts with many cellular proteins to transform cells. Several other polyomaviruses also express a LT protein that is required for transformation; however, previous research has hinted that these polyomavirus LTs may not transform cells by the same mechanisms. The aim of this work is to uncover the differences in molecular mechanisms of transformation by LTs of two human polyomaviruses, BKV and JCV, and a primate polyomavirus, LPV, as compared to SV40 LT.
The LT proteins contain discrete structural domains that are also associated with different functions of the protein. These domains can be removed to isolate individual functions without greatly altering those functions. Expression of a short fragment of the LT antigens known to interact with the cell cycle regulating family of pRB proteins showed that this region confers the same transformation capabilities between the four polyomaviruses. The BKV and JCV fragments, however, also conferred a growth advantage in the dense focus assay, suggesting additional activities of this region of BKV and JCV LT other than pRB inhibition. In a separate line of investigation, a region of LT that is only present in SV40, BKV, and JCV LTs known as the variable linker and host range region (VHR) was removed. Very little is known about how this region of LT effects transformation. Transformation assessed by growth in low serum was reduced by VHR truncation of the SV40, but not the JCV, LT. Conversely, anchorage independent transformation was enhanced only by truncation of the JCV VHR. This is the first report to link the SV40 or JCV VHR region to transformation potential. Expression of the both VHR LT truncations resulted in changes in T antigen expression and cellular p53 post-translational modifications but interaction with the pRB pathway was unaffected. Future studies will focus on identifying the cellular protein interactions with each LT domain that contribute to the differences in transformation identified here.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Seneca, Nicolenis23@pitt.eduNIS23
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberDeLuca, Neal Andeluca@pitt.eduNDELUCA
Committee MemberGrabowski, Paula Jpag4@pitt.eduPAG4
Committee MemberKinchington, Paul R.kinch@pitt.eduKINCH
Committee MemberKhan, Saleem Akhan@pitt.eduKHAN
Committee ChairPipas, James Mpipas@pitt.eduPIPAS
Date: 5 December 2014
Date Type: Publication
Defense Date: 18 September 2014
Approval Date: 5 December 2014
Submission Date: 4 December 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 160
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cancer viruses, polyomavirus, cancer biology
Date Deposited: 05 Dec 2014 15:41
Last Modified: 15 Nov 2016 14:25


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