) The Kaposi's sarcoma-associated herpesvirus (KS or human herpesvirus 8 (HHV 8) is consistently present in Kaposi's sarcoma and primary effusion (body cavity-based) lymphoma, two malignancies frequently found in patients with AIDS. The applicant has identified and sequenced two genes within this virus that appear to represent viral oncogenes since they encode proteins homologous with cellular proteins that are involved in cell cycle control. These genes encode a G protein-coupled receptor (GCR) and a cyclin D homolog, respectively. Both genes are expressed at the RNA level in Kaposi's sarcoma and primary effusion lymphoma. The principal objective of the studies proposed is to characterize the KSHV GCR and cyclin proteins structurally and functionally in order to assess their role in oncogenesis. The first specific aim is to analyze the pattern of protein expression and regulation of both the KSHV GCR and cyclin in KSHV-positive tissues and cell lines using antibodies prepared against the purified proteins. The clinical usefulness of these antibodies in the histologic diagnosis of the various KSHV-associated diseases will be evaluated. The second specific aim of this application is to characterize the KSHV GCR functionally by confirming preliminary evidence that interleukin 8 is a ligand for this receptor and determining whether an autocrine loop or paracrine loop and/or constitutive receptor activation are mechanisms involved in KSHV-mediated transformation. The applicant will also characterize the subsequent pathways involved in signal transduction by the KSHV GCR. The third specific aim is to analyze the role of the KSHV cyclin in cell cycle progression. The study will determine which cyclin-dependent kinases are associated with this viral cyclin and whether this association leads to protein kinase activity resulting in Rb protein phosphorylation. The regulation of these complexes by cyclin-dependent kinase inhibitors, including pl6 (INK4a), p2l and p27 (Kip1), will be evaluated. These experiments will lead to a better understanding of the mechanisms employed by KSHV in the development of Kaposi's sarcoma and malignant lymphoma, the two malignancies most frequently associated with HIV infection, and will contribute to the general knowledge of human oncogenic viruses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073531-03
Application #
2748915
Study Section
Special Emphasis Panel (SRC (C2))
Program Officer
Cremer, Kenneth J
Project Start
1996-09-30
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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Cannon, Mark; Philpott, Nicola J; Cesarman, Ethel (2003) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol 77:57-67
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Keller, S A; Schattner, E J; Cesarman, E (2000) Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96:2537-42
Cesarman, E; Mesri, E A (1999) Virus-associated lymphomas. Curr Opin Oncol 11:322-32
Cesarman, E; Chadburn, A; Liu, Y F et al. (1998) BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome. Blood 92:2294-302
Reed, J A; Nador, R G; Spaulding, D et al. (1998) Demonstration of Kaposi's sarcoma-associated herpes virus cyclin D homolog in cutaneous Kaposi's sarcoma by colorimetric in situ hybridization using a catalyzed signal amplification system. Blood 91:3825-32
Matolcsy, A; Nador, R G; Cesarman, E et al. (1998) Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation. Am J Pathol 153:1609-14
Geras-Raaka, E; Arvanitakis, L; Bais, C et al. (1998) Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture. J Exp Med 187:801-6

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