The human herpesvirus 8 (HHV8) has been associated with three neoplasms: primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman' s disease in human immunodeficiency virus (HIV)-related and -unrelated cases. In addition, there is evidence that HHV8 may be present in the bone marrow of multiple myeloma patients. While HHV8 is not ubiquitous in the general population (10-15 percent seroprevalence), evidence of exposure to HHV8 is quite high (60-70 percent) in the homosexual HIV-positive population. One common feature amongst all HHV8-associated neoplasms is that they utilize interleukin 6 (IL-6) as a tumor growth factor. IL-6 may also facilitate HIV infection, as it induces the proliferation of HTV in HIV infected monocytes and CD4-positive T cells. Thus, we initially hypothesized that an HFIV8 encoded protein upregulates IL-6 expression. In preliminary data we successfully demonstrated that the HHV8 latent proteins, latency associated nuclear antigen (LANA) and Fas associated death domain like interferon converting enzyme inhibitory protein (vFLIP), upregulate cellular IL-ti expression. We have shown that LANA transactivates the IL-6 promoter through the API response element, LANA directly binds to the APi response element, and vFLIP functions through activation of the NF-kappaB and APi transcription factors. Furthermore, vFLIP potentiates LANA-induced IL-6 expression and vice versa. In this proposal, our specific aims are: 1. Elucidate the relevant DNA-protein interactions involved in LANA-mediated transactivation of the LL-6 promoter. 2. Identify the protein-protein interactions involved in LANA transactivation of the IL-6 promoter. 3. Establish the importance of vFLIP and LANA in the induction of IL-6 expression as well as proliferation and inhibition of apoptosis in endogenously HHVS-infected cells, and characterize the molecular interactions between vFLIP and LANA that result in their reciprocal potentiation of IL-6 induction. Our long-term objective is to identify the molecular mechanisms involved in HHVS -mediated upregulation of cellular IL-6 production. The identification of the specific domains of LANA or vFLIP that are involved in the augmentation of IL-ti expression might provide a natural target for drug development to inhibit the effects of these proteins in HHV8 infected malignant cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080004-04
Application #
6858600
Study Section
Pathology B Study Section (PTHB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-03-15
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
4
Fiscal Year
2005
Total Cost
$232,750
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
An, Jiabin; Mo, Deqiong; Liu, Huiren et al. (2008) Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation. Cancer Cell 14:394-407
An, Jiabin; Sun, Yiping; Rettig, Matthew B (2004) Transcriptional coactivation of c-Jun by the KSHV-encoded LANA. Blood 103:222-8
An, J; Sun, Y; Fisher, M et al. (2004) Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia 18:1699-704
An, Jiabin; Sun, Yiping; Sun, Ren et al. (2003) Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and JNK/AP1 pathways. Oncogene 22:3371-85