SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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V I R A L O N C O L O G Y P R O G R A M trial. His data demonstrate that IFN α potently induces the death receptor ligand TRAIL. AZT is phosphorylated by the herpes virus thymidine kinase and acts by blocking NF-κB (p50, p65) translocation into the nucleus allowing for an unopposed death signal. AZT also down-regulates the expression of anti-viral, anti-apoptotic proteins such as vFLIP. A similar mechanism has been shown to occur in other viral-induced tumors such as post-transplant lymphoma (EBV). Dr. Harrington and his colleagues have initiated a new clinical trial for HHV-8-associated lymphomas that utilizes parenteral AZT and IFN α (these tumors virtually are always fatal). The first patient enrolled has remained in complete remission for more than two years. AZT-mediated blockade of NF-κB is a potentially exciting novel strategy that combines both anti-HIV and EBV activity. The target malignancy (and one of the most common worldwide) for this type of approach is endemic Burkitt’s lymphoma. Current studies focus on understanding the specificity of this therapy for herpes virus-associated lymphomas, the development of more potent antiviral antilymphoma thymidine analogues, and the extension of this approach to other gamma herpes and lymphomas that occur in the immunocompromised patients (post-transplant, hereditary immunodeficiencies). This work is done in collaboration with Abdul M. Mian, Ph.D., and Ram Agarwal, Ph.D. Dr. Harrington also recently received a NCI-funded career award (K24), which will enable him to focus on the above described laboratory and clinical studies. • Antero G. So, M.D., Ph.D., and Kathleen M. Downey, Ph.D., recently have identified a novel protein, polymerase delta interacting protein (PDIP1). This protein interacts with the small subunit (p50) of DNA polymerase delta (the primary polymerase responsible for cell growth and differentiation) and the proliferating cell nuclear antigen (PCNA). PDIP1 colocalizes with pol delta and PCNA at replication foci in the nuclei of S-phase cells and stimulates its activity (in the presence of PCNA). The expression of PDIP1 can be induced by the cytokines tumor necrosis factor alpha (TNF-α) and IL-6. PDIP1 is a distal target of IL-6. There is increasing evidence suggesting that the cytokine IL-6 plays an important role in the pathogenesis of certain types of AIDS-related lymphomas. Recent studies strongly have implicated a critical role for IL-6 in EBV-dependent lymphoproliferative disease. It also has been reported that the development of AIDS-associated Burkitt’s/small non-cleaved cell lymphoma is preceded by elevated serum levels of IL-6. In addition, cell lines derived from HHV-8-associated AIDS primary effusion lymphomas constitutively secrete high levels of both IL-6 and the HHV-8 IL-6 homologue (vIL-6). Consistent with these findings is the observation that the inhibition of NF-κB (by AZT or other inhibitors) down-regulates cytokine IL-6 and induces apoptosis in Karposi’s sarcoma-associated herpes virus (KSHV) infected cells. • Researchers in Lawrence H. Boise, Ph.D.’s laboratory investigate factors that regulate the pathways associated with death receptor-induced apoptosis. Previous studies have indicated that cells can utilize one of two pathways to propagate death signals resulting from the ligation of the TNF receptor as well as from CD95 (Fas/ Apo-1). Cells referred to as type I cells can activate a caspase cascade that does not require release of factors from the mitochondria. Expression of anti-apoptotic proteins Bcl-2 or Bcl-x L is incapable of inhibiting death receptor signaling in type I cells. In contrast, death receptor signaling in type II cells requires release of mitochondrial factors and is inhibited by Bcl-2/x L expression. Dr. Boise has demonstrated that cells can utilize both type I and type II signals and that Bcl-2/x L can affect type I death receptor signaling when used in concert with inhibitors of signaling caspases. Interestingly, γ- herpes viruses associated with Karposi’s sarcoma and PELs encode both a Bcl-2 homologue as well as an inhibitor of CD95 signaling (vFlip). While it has been previously suggested that viruses express these molecules to block distinct UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 131
V I R A L O N C O L O G Y P R O G R A M death pathways, based on his results it is hypothesized that vBcl-2 and vFlip may work in concert to block complex death receptor signaling. Researchers currently are testing this hypothesis through the introduction of these genes into TNF-α-sensitive cell lines as well as inhibiting expression of virally expressed genes in PEL cell lines. This work is being carried out primarily by M.D./Ph.D. student Esther Obeng. Ms. Obeng has received a Howard Hughes Medical Institute Fellowship to support her research. This work is the basis of collaboration with William J. Harrington, Jr., M.D., on his studies to determine the mechanisms of anti-viral induced apoptosis in AIDS-related lymphomas that appear to be death receptor mediated. • Beatriz M.A. Fontoura, Ph.D.’s laboratory works on the signal-mediated nuclear import and export of molecules that occurs through nuclear pore complexes (NPC). These are highly regulated pathways that control nuclear entry and exit of molecules such as transcription factors, RNAs, kinases, and viral particles. NPCs are composed of proteins termed nucleoporins or Nups, which have a role in the structure of the NPC and also in regulating translocation of molecules through the NPC. Nups are targets of viral proteins and disruption of Nup function is involved in cancer. Dr. Fontoura has identified and characterized two major Nups—Nup98 and Nup96—which are key controllers of nuclear entry and exit of proteins and RNAs. The Nup98-Nup96 pathway is highly regulated by specific signaling pathways, is a target of viral proteins, and is involved in tumorigenesis. The goal of the investigators working in this laboratory is to understand the molecular mechanisms of the nuclear transport machinery and how they are regulated by different signaling pathways and viruses. The discovery of novel mechanisms or factors of this pathway are important for controlling cell growth and also may serve as therapeutic targets. • Edward W. Harhaj, Ph.D.’s laboratory studies viral-induced malignancy by the human T-cell leukemia virus type I (HTLV-I). HTLV-I is associated with several diseases including adult T- cell leukemia (ATL) and a neurological disorder known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLC-I encodes a trans-activating protein, Tax, which has pleiotropic functions and is highly oncogenic. Tax activates cellular signaling pathways and transcription factors, such as NF-κB, resulting in global changes in gene expression. NF-κB is a family of dimeric DNA-binding proteins that regulates the expression of genes that control a variety of cellular functions such as activation, differentiation, survival, and effector function. A major effort of Dr. Harhaj’s laboratory is to elucidate the mechanisms utilized by Tax to activate the NF-κB signaling pathway. Toward this end, researchers are identifying cellular proteins that interact with Tax and are examining the role of these proteins in Tax-medicated NF-κB activation and cellular transformation. An example of how the laboratories interact is demonstrated in the illustration on page 133. Each group addresses a distinct area relevant to viral lymphomagenesis. Training and International Effort The laboratories of Dr. Harrington and Charles Wood, Ph.D., (University of Nebraska) have a long-standing relationship in AIDS-associated malignancies and currently collaborate on two R01-funded research projects and two Fogarty International Training Programs. These research projects center around the molecular epidemiology of the transmission of HHV-8 and EBV and the role these viruses play in the induction of malignancies. The objectives of these projects are: 1) determine the factors associated with transmission of HHV-8 in Zambia and its relationship on progression to AIDS, 2) develop an NCI-sponsored research repository in Brazil and Africa, 132 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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