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Identification and Functional Characterization of Estrogen Response Elements in the Human Herpesvirus 8 Genome

Shea, Patrick Ryan (2008) Identification and Functional Characterization of Estrogen Response Elements in the Human Herpesvirus 8 Genome. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Interaction between viral infection and host genetic susceptibility has increasingly become recognized as an important factor in the etiology of human cancer. Epidemiologic studies suggest that prostate cancer is a complex disease involving host genetic factors and environmental exposures that modify risk. Here we report a novel interaction between infection with human herpesvirus 8 (HHV8) and the human estrogen receptor alpha XbaI polymorphism which is associated with an increased risk of prostate cancer (p=0.032; OR=3.10 95%CI (1.42-6.77)) in an Afrocaribbean population from Tobago. HHV-8 is the causative agent in Kaposi's sarcoma (KS). Despite similar HHV-8 seroprevalences, KS lesions are much less common in females, suggesting that sex hormones influence KS pathology. The estrogen receptor (ER) is a ligand-dependant transcription factor that mediates the genomic effects of hormone signaling. Because of the suggested role of sex hormones in KS development and prostate cancer risk, we hypothesized that some HHV-8 genes might be activated by ER. We computationally scanned the HHV-8 genome for estrogen response elements (EREs). Our analysis identified high scoring EREs in the promoter regions of several genes in the HHV-8 genome, including the regulatory gene K8. Binding of ERs to HHV-8 EREs was confirmed by electrophoretic mobility shift assay and ELISA. To demonstrate that HHV-8 EREs were functional, promoter regions were cloned into reporter plasmids and luciferase expression measured with and without estradiol. Our results demonstrated increased reporter transcription in response to estrogens in cells expressing ERα. Further, we analyzed other gammaherpesviruses and identified several conserved EREs, including high-scoring EREs in the promoter of the EBV homolog of K8. These results indicate that estrogen may influence transcription from the HHV-8 genome, outside of the normal viral transcription pathway. Our findings may help to explain the differential risk of KS and could represent an important regulatory pathway in other gammaherpesviruses. Prostate cancer and KS present a tremendous burden on public health, not only in the US, but worldwide. Insights into the pathogenesis of these diseases may help us to understand their basic biology and provide potential screening and therapeutic targets.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shea, Patrick Ryanpatrickrshea@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFerrell, Robert Erferrell@pitt.eduRFERRELL
Committee MemberBunker, Clareann Hbunkerc@edc.pitt.eduBUNKERC
Committee MemberJenkins, Frank Jfjenkins@pitt.eduFJENKINS
Committee MemberBenos, Panayiotis Vbenos@pitt.eduBENOS
Date: 26 September 2008
Date Type: Completion
Defense Date: 3 June 2008
Approval Date: 26 September 2008
Submission Date: 13 June 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: estrogen; herpesvirus; hhv8; hormones; host pathogen interaction; kshv
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06132008-145343/, etd-06132008-145343
Date Deposited: 10 Nov 2011 19:47
Last Modified: 15 Nov 2016 13:44
URI: http://d-scholarship.pitt.edu/id/eprint/8097

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