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Role of IRF4 in the Regulation of Cellular Interferon Stimulated Genes and KSHV Lytic Gene Expression in Primary Effusion Lymphoma

Forero Rueda, Adriana (2014) Role of IRF4 in the Regulation of Cellular Interferon Stimulated Genes and KSHV Lytic Gene Expression in Primary Effusion Lymphoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The interferon regulatory factors (IRF) are a family of transcription factors that control intrinsic cellular responses to viral infections. The regulation of target gene expression by IRF proteins is mediated by binding to interferon-stimulated response elements (ISRE) DNA motifs located in the 5’ regulatory region of Interferon-stimulated genes (ISGs). Interferon regulatory factor 4 (IRF4), a hematopoietic-specific transcription factor, is a potential dual regulator of ISRE-mediated gene expression although its transcriptional signature is still poorly understood. Primary effusion lymphoma (PEL), a rare B-cell malignancy is characterized by the expression of high level of cellular IRF4, a disrupted B-cell transcriptional program, and latent infection with Kaposi’s sarcoma-associated herpesvirus (KSHV). The goal of this study is to elucidate the ability of IRF4 to alter the transcriptional expression of ISRE and ISRE-like sequence regulated genes in the absence of B-cell specific binding partners. Small-scale gene expression assays showed that IRF4 is capable of differentially regulating the expression of ISRE-responsive genes. The positive regulation of IRF4 target genes (ISG60 and Cig5) was shown to be in response to direct binding of IRF4 to chromatin regions corresponding to ISRE-motifs located at the 5’ promoter regulator regions of ISG60 and Cig5. To understand the role of IRF4 beyond cellular gene expression, we tested KSHV-encoded latency associated genes that modulated IRF4-mediated gene expression. We identified the viral FLICE inhibitory protein (vFLIP) as an enhancer of IRF4-mediated ISG induction and showed that this function is dependent on the activation of NF-kB. Finally, we examined the role of IRF4 in the regulation of lytic gene expression. The replicator and transcription activator (RTA) protein, is a sequence specific transcription factor that regulates the expression of a subset of early genes through binding ISRE-like motifs on their promoters. Studies aimed at understanding the consequences of IRF4
expression in PEL cells showed that IRF4 acts as a negative regulator of lytic gene expression by inhibiting RTA expression and RTA-mediated gene transactivation. These data support a model in which IRF4 mediates an antiviral cellular response, inhibiting lytic replication of KSHV while contributing to the transformative effects of KSHV by promoting viral latency.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Forero Rueda, Adrianaadf16@pitt.eduADF16
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSarkar, Saumen N.saumen@pitt.eduSAUMEN
Committee MemberBorghesi, Lisaborghesi@pitt.eduBORGHESI
Committee MemberCoyne, Carolyn Bcoynec2@pitt.eduCOYNEC2
Committee MemberDeLuca, NealNdeluca@pitt.eduNDELUCA
Committee MemberKhan, Saleemkhan@pitt.eduKHAN
Date: 28 January 2014
Date Type: Publication
Defense Date: 4 December 2013
Approval Date: 28 January 2014
Submission Date: 24 January 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 211
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: KHSV; Interferon regulatory Factor; Interferon Stimulated Genes; Primary effusion lymphoma
Date Deposited: 28 Jan 2014 17:18
Last Modified: 15 Nov 2016 14:17


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