Infection with the human herpes virus 8 (HHV8) has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multi-centric Castleman's disease, angio-immunoblastic lymphadenopathy with dysproteinemia, and multiple myeloma. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. Although HHV8 has been found to encode homologs of several cellular oncogenes and growth factors, almost all of them lack expression in latently infected KS and PEL cells, thereby arguing against their casual role in the pathogenesis of these disorders. We have discovered that orf-K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein), is capable of blocking apoptosis induced by death receptors belonging to the Tumor Necrosis Factor Receptor (TNFR) family. More importantly, orf-K13 is capable of activating the NF-kappaB pathway, which has been previously implicated in the pathogenesis of EBV (Epstein Barr virus)- and HTLV1 (Human T cell Leukemia virus 1)- associated lymphoproliferative disorders. As orf-K13 is one of the few HHV8 encoded proteins which are expressed in latently infected KS and PEL cells, the above results make it an ideal candidate for causing the cellular transformation associated with infection by HHV8. The overall objective of this proposal is to test the above hypothesis using in vitro and in vivo models.
In aim 1, biochemical and molecular characterization of the mechanisms underlying the NF-kappaB activating ability of orf-K13 will be carried out with the hope of identifying the interactions critical for this activity.
In aim 2, biological consequences of orf-K13 mediated NF-kappaB will be studied and its effect on cellular activation, proliferation and transformation characterized.
Aim 3 will focus on further characterization of the anti-apoptotic properties of orf-K13 and its biological consequences.
In aim 4, transgenic approach will be used to study the in vivo role of orf-K13 in the pathogenesis of AIDS- related malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085177-02
Application #
6377585
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
2
Fiscal Year
2001
Total Cost
$241,213
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Yang, Yanqiang; Groshong, Jason S; Matta, Hittu et al. (2011) Constitutive NF-kappaB activation confers interleukin 6 (IL6) independence and resistance to dexamethasone and Janus kinase inhibitor INCB018424 in murine plasmacytoma cells. J Biol Chem 286:27988-97
Matta, Hittu; Gopalakrishnan, Ramakrishnan; Punj, Vasu et al. (2011) A20 is induced by Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 and blocks K13-induced nuclear factor-kappaB in a negative feedback manner. J Biol Chem 286:21555-64
Liu, Ren; Gong, Ming; Li, Xiuqing et al. (2010) Induction, regulation, and biologic function of Axl receptor tyrosine kinase in Kaposi sarcoma. Blood 116:297-305
Liu, Ren; Li, Xiuqing; Tulpule, Anil et al. (2010) KSHV-induced notch components render endothelial and mural cell characteristics and cell survival. Blood 115:887-95
Ahmad, Anwaar; Groshong, Jason S; Matta, Hittu et al. (2010) Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 cooperates with Myc to promote lymphoma in mice. Cancer Biol Ther 10:1033-40
Punj, V; Matta, H; Schamus, S et al. (2010) Kaposi's sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a. Oncogene 29:1835-44
Punj, Vasu; Matta, Hittu; Schamus, Sandra et al. (2009) Induction of CCL20 production by Kaposi sarcoma-associated herpesvirus: role of viral FLICE inhibitory protein K13-induced NF-kappaB activation. Blood 113:5660-8
Matta, H; Punj, V; Schamus, S et al. (2008) A nuclear role for Kaposi's sarcoma-associated herpesvirus-encoded K13 protein in gene regulation. Oncogene 27:5243-53
Zhao, Jinshun; Punj, Vasu; Matta, Hittu et al. (2007) K13 blocks KSHV lytic replication and deregulates vIL6 and hIL6 expression: a model of lytic replication induced clonal selection in viral oncogenesis. PLoS One 2:e1067
Matta, Hittu; Mazzacurati, Lucia; Schamus, Sandra et al. (2007) Kaposi's sarcoma-associated herpesvirus (KSHV) oncoprotein K13 bypasses TRAFs and directly interacts with the IkappaB kinase complex to selectively activate NF-kappaB without JNK activation. J Biol Chem 282:24858-65

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