Kaposi's sarcoma-associated virus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The KSHV genome encodes a protein named K1 that has been shown to activate B cell signaling pathways and transform cells. The K1 gene is encoded by the first open reading frame of KSHV and is in an equivalent genomic position as HVS STP and RRV R1. The proposed study is directed towards understanding the functional role of the KSHV K1 protein. We will investigate the molecular mechanism of deregulation of cell growth control induced by the KSHV K1 protein. We have previously shown that K1 can upregulate angiogenic factors and protect cells from Fas-mediated apoptosis. Our hypothesis is that the signaling function of K1 plays a significant role in KSHV-associated pathogenesis through a paracrine mechanism. We propose to characterize the mechanism of K1 signaling and determine how it protects cells from apoptosis. We will also investigate how K1 signaling is regulated at the molecular level. Additionally, signaling by K1 may be needed to activate the cell and enhance viral replication. Hence we will also investigate the role of K1 in viral lytic replication. Thus, we propose to analyze the detailed biochemical mechanisms of K1 function, as well as to assess the biological role of K1 in the lifecycle of the virus. The proposed studies will provide significant and biologically relevant insights into the functions of this viral gene.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096500-09
Application #
7858396
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$279,757
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Damania, Blossom (2016) A Virological Perspective on Cancer. PLoS Pathog 12:e1005326
Ma, Zhe; Damania, Blossom (2016) The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell Host Microbe 19:150-8
Dittmer, Dirk P; Damania, Blossom (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126:3165-75
Johnson, Amy R; Qin, Yuanyuan; Cozzo, Alyssa J et al. (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5:506-26
Anders, Penny M; Zhang, Zhigang; Bhende, Prasana M et al. (2016) The KSHV K1 Protein Modulates AMPK Function to Enhance Cell Survival. PLoS Pathog 12:e1005985
Anders, Penny; Bhende, Prasanna M; Foote, Michael et al. (2015) Dual inhibition of phosphatidylinositol 3-kinase/mammalian target of rapamycin and mitogen activated protein kinase pathways in non-Hodgkin lymphoma. Leuk Lymphoma 56:263-6
Giffin, Louise; West, John A; Damania, Blossom (2015) Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Modulates Endothelial Cell Movement by Upregulating Cellular Genes Involved in Migration. MBio 6:e01499-15

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