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Abstract
Grant Number: 1R01CA103646-01A1 Project Title: KSHV vFLIP in B cell survival
PI Information: Name Title CESARMAN, ETHEL ecesarm@med.cornell.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): KSHV/HHV-8 is clearly etiologically associated with Kaposi's sarcoma. This virus can be found in the B cells of infected individuals, both in the circulation and mantle zones of lymph nodes. In addition it is present in B cells in a large proportion of multicentric Castleman's disease as well as in B cell lymphomas, specifically primary effusion lymphomas (PEL) and a subset of large cell non-Hodgkin's lymphomas in HIV-positive individuals not involving body cavities. While KSHV-infection is not sufficient for the development of these disorders, the specific association suggests that KSHV plays a role in their pathogenesis. We hypothesize that that vFLIP is a critical mediator of this oncogenic consequence of viral infection. In support of this hypothesis our preliminary data indicates that vFLIP activates NF-KappaB in B cells, that NF-KappaB activity is essential for the survival of PEL cells, and that vFLIP is largely responsible for the constitutive NF-KB activity seen in latently infected lymphoma cells. We propose that vFLIP protects cells from apoptosis by a two pronged effect on TNF-signaling pathways: first directly by interfering with the activation and function of the death-inducing signaling complex (DISC), and second indirectly by forming a life-inducing signaling complex (LISC) which leads to NF-KappaB activation, in turn inducing expression of anti-apoptotic genes. We will test this model and determine the role of vFLIP in the survival of B cells through the following specific aims: 1) Characterize the role of vFLIP in PEL cell survival; 2) Perform a structural and functional characterization of vFLIP activity in B cells; and 3) Assess vFLIP function in vivo. These studies will lead to a detailed understanding of the contribution of KSHV vFLIP to the survival of infected B cells and lymphomagenesis, and validate vFLIP as a therapeutic target for the treatment of primary effusion lymphoma and perhaps other KSHV-associated diseases.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
B cell lymphoma, B lymphocyte, human herpesvirus 8, neoplasm /cancer genetics, nuclear factor kappa beta, protein structure function, virus genetics, virus protein, virus related neoplasm /cancer
Kaposi's sarcoma, nonHodgkin's lymphoma, tumor necrosis factor alpha, viral carcinogenesis, virus infection mechanism
NOD mouse, RNA interference, SCID mouse, cell line, genetically modified animal, human genetic material tag, neoplasm /cancer transplantation
Institution: WEILL MEDICAL COLLEGE OF CORNELL UNIV 1300 YORK AVENUE NEW YORK, NY 10021 Fiscal Year: 2004 Department: PATHOLOGY AND LABORATORY MEDICINE Project Start: 01-MAY-2004 Project End: 30-APR-2009 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1