Publication Date

2018-09-29

Availability

Embargoed

Embargo Period

2020-09-28

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2018-08-24

First Committee Member

Noula Shembade

Second Committee Member

Wasif N. Khan

Third Committee Member

Enrique A. Mesri

Fourth Committee Member

Savita Pahwa

Fifth Committee Member

Xiangxi Xu

Abstract

Approximately 15% of human cancers worldwide, including leukemias and lymphomas, are caused by infection from oncogenic viruses, such as human T-cell lymphotropic virus 1 (HTLV-1) and Kaposi's sarcoma herpesvirus (KSHV). Oncogenes of these viruses, such as Tax of HTLV-1, and viral G-protein coupled receptor (vGPCR) and viral FLICE inhibitory protein (vFLIP) of KSHV, maintain persistent inflammation via activation of NF-kB, a family of transcription factors. NF-kB is normally transiently activated in response to TNF, IL-1, and bacteria or viral infections. However, under certain pathologic conditions, such as inflammation or tumorigenesis, it is chronically activated. Here we show host factor Cell Adhesion Molecule 1 (CADM1) expression is significantly upregulated in primary human PBMCs infected with HTLV-1 or KSHV viruses. Viral oncogenes Tax, vGPCR, and vFLIP usurp host factor CADM1 to maintain chronic activation of NF-kB. Tax, vGPCR, and vFLIP interact with the cytoplasmic tail of CADM1 to maintain chronic activation of NF-kB in infected cells. Furthermore, NF-kB activation by Tax and vFLIP is initiated in the plasma membrane lipid rafts of HTLV-1 and KSHV-infected cells, respectively. In addition, CADM1 is critical for the proliferation and survival of KSHV-associated Primary Effusion Lymphoma (PEL) cells. These results strongly suggest that CADM1 plays key roles in HTLV-1 and KSHV-mediated tumorigenesis and may lead to the development of novel therapies.

Keywords

Oncogenic virus; NF-kB; oncogene; inflammation; HTLV-1; KSHV

Available for download on Monday, September 28, 2020

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