Retroviruses have provided great insights into the process of carcinogenesis. In the past, studies on retroviral carcinogenesis have elucidated such important principles as viral oncogenes and insertional activation of cellular proto-oncogenes. Retroviruses are also useful for studying the multi-step process of carcinogenesis, since they induce specific tumors with predictable latencies. Moloney murine leukemia, virus (M-MuLV) induces T-lymphoma with a latency of 3-4 months when injected into mice. In this proposal, we will continue our experiments on mechanism of leukemogenesis by M-MuLV. We will address three aims. 1) We will continue to map the initial cellular pathways of infection, from the initially infected cells through the bone marrow to the thymus. We will take advantage of replication-defective, helper-free M-MuLV-based vectors expressing a readily detectable reporter gene (beta-gal). Infection of mice mutant in development of myeloid cells or hair follicles, and adoptive transfer experiments will address the mechanisms of the spread of infection. 2) We will investigate the role of glycosylated gag protein in M-MuLV infection in vivo. We previously studied the synthesis of glycosylated gag protein, and generated a glycosylated gag-negative M-MuLV mutant (Ab-X-M-MuLV). In vivo infections with this mutant indicate that glycosylated gag is important for M-MuLV infection in vivo. Moreover, SC inoculation of the mutant shows a delay in leukemogenesis, and the tumors show lower levels of infectivity. We will employ genetic and biochemical means to study the role of glycosylated gag in M-MuLV infection in vivo. 3) We will study the basis of tissue-specific expression of the M-MuLV long terminal repeat (LTR), the major determinant in MuLV disease specificity. Other investigators have extensively mapped nuclear factor binding sites within the M-MuLV, but it has been unclear if those proteins are bound in vivo. We have applied in vivo footprinting and ligation-mediated PCR (LMPCR) to map factor binding to the M-MuLV LTR in infected cells. We will now map factor binding in the upstream and downstream LTRs, and we will characterize factor binding to wild-type or interesting variant LTRs in different cell types where there is high-level vs. low expression. Together, these experiments will provide new and important insights into leukemogenesis by MuLVs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Cole, John S
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University of California Irvine
Schools of Arts and Sciences
United States
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Low, Audrey; Datta, Shoibal; Kuznetsov, Yurii et al. (2007) Mutation in the glycosylated gag protein of murine leukemia virus results in reduced in vivo infectivity and a novel defect in viral budding or release. J Virol 81:3685-92
Jahid, Sohail; Bundy, Linda M; Granger, Steven W et al. (2006) Chimeras between SRS and Moloney murine leukemia viruses reveal novel determinants in disease specificity and MCF recombinant formation. Virology 351:7-17
Kuznetsov, Y G; Low, A; Fan, H et al. (2005) Atomic force microscopy investigation of isolated virions of murine leukemia virus. J Virol 79:1970-4
Kuznetsov, Y G; Low, A; Fan, H et al. (2004) Atomic force microscopy investigation of wild-type Moloney murine leukemia virus particles and virus particles lacking the envelope protein. Virology 323:189-96
Datta, S; Kothari, N H; Fan, H (2001) Induction of Tax i expression in MT-4 cells by 5-azacytidine leads to protein binding in the HTLV-1 LTR in vivo. Virology 283:207-14
Granger, S W; Fan, H (2001) Purification of Moloney murine leukemia virus chromatin from infected cells by an affinity method. J Biomed Sci 8:278-89
Bonzon, C; Fan, H (2000) Moloney murine leukemia virus-induced tumors show altered levels of proapoptotic and antiapoptotic proteins. J Virol 74:8151-8
Datta, S; Kothari, N H; Fan, H (2000) In vivo genomic footprinting of the human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat enhancer sequences in HTLV-1-infected human T-cell lines with different levels of Tax I activity. J Virol 74:8277-85
Granger, S W; Bundy, L M; Fan, H (1999) Tandemization of a subregion of the enhancer sequences from SRS 19-6 murine leukemia virus associated with T-lymphoid but not other leukemias. J Virol 73:7175-84
Lander, J K; Chesebro, B; Fan, H (1999) Appearance of mink cell focus-inducing recombinants during in vivo infection by moloney murine leukemia virus (M-MuLV) or the Mo+PyF101 M-MuLV enhancer variant: implications for sites of generation and roles in leukemogenesis. J Virol 73:5671-80

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