Hung Y. Fan
Molecular Biology & Biochemistry
School of Biological Sciences
Phone: (949)824-5554
Email: hyfan@uci.edu
http://www.faculty.uci.edu/profile.cfm?faculty_id=2118
Hung Fan
Dr. Fan’s research is focused on retroviruses. Retroviruses have been of interest because they cause human diseases including cancer and AIDS; also study of oncogenic animal retroviruses has provided important insights into basic mechanisms of carcinogenesis (e.g. discovery of oncogenes and proto-oncogenes). Dr. Fan is investigating several oncogenic retroviruses. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of a transmissible lung cancer in sheep (ovine pulmonary adenocarcinoma or OPA). His lab was the first to isolate an infectious and oncogenic molecular clone of JSRV, and they have used it to develop essential biological biological reagents for study of this virus. Three areas with regard to JSRV are being studied. First, JSRV is unique in that its envelope protein functions as an oncogene. Current studies include mapping domains of the protein involved in transformation, identifying cellular proteins that are involved in the transformation, studying transformation of primary lung type II pneumocytes by JSRV Env, determining the solution structure of the cytoplasmic tail of the transmembrane (TM) protein, and developing transgenic mice expressing JSRV Env as a tumorigenesis model. The second area of JSRV research investigates the transcriptional specificity of the virus. Studies have shown that the JSRV long terminal repeat (LTR) is quite specific for lung epithelial cell lines, and cellular transcription factors involved in this specificity include HNF-3, NF-1 and C/EBP. The particular isoforms of these factors involved in transcription in lung epithelial cells are of interest. Transgenic mice expressing the beta-galactosidase reporter gene under control of the JSRV LTR have also been established to determine LTR specificity in vivo. The third area of JSRV research involves a novel regulatory factor encoded by the virus, Rej. Rej resembles regulatory factors encoded by other retroviruses, including the Rev factor of HIV-1 and the Rem factor of MMTV. Rej, which is encoded in the 5’ end of the env gene, is required for expression of viral Gag and Pol protein from unspliced viral RNA. However, unlike the other analogous regulatory proteins, Rej does not influence export of unspliced viral RNA. This suggests that Rej may function to influence the ability of unspliced viral mRNA to be translated.
Dr. Fan’s laboratory is also investigating murine leukemia viruses. A long-standing interest has been pathogenesis and in vivo infectivity by Moloney murine leukemia virus (M-MuLV). Current studies are focused on the role of an alternative form of Gag polyprotein, glycosylated Gag (glyco-gag) in M-MuLV replication. Recent experiments indicate that glyco-Gag facilitates efficient virus particle production at a very late stage in the infection process (budding or release). Cellular factors involved in this process are being investigated, as well as the mechanism of action. Another topic is restriction of M-MuLV replication in vivo by the murine APOBEC3 (mA3) protein. The APOBEC3 family of proteins has been shown to restrict infection by a variety of retroviruses, most notably HIV. In collaboration with Drs. Matija Peterlin (UCSF) and Susan Ross ( U. of Pennsylvania), studies employing an mA3 knock-out mouse are being conducted. mA3 knock-out mice show higher rates of in vivo infection and leukemogenesis by M-MuLV than wild-type mice. The mechanisms of this restriction are being investigated.
Another MuLV-related virus being investigated is a novel virus (XMRV-1) detected in human prostate cancer tissues from individuals with an inherited predisposition to the disease (carrying the R468Q variant of RNAseL). While the virus was originally detected in humans, the fact that it is closely related to endogenous xenotropic MuLVs suggests that it should replicate in non-murine rodent cells. Experiments on XMRV-1 infection in rat cells and rats are in progress.
Selected Publications:
Maeda, N., Palmarini, M., Murgia, C., and Fan, H. (2001). Direct transformation of rodent fibroblasts by jaagsiekte sheep retrovirus DNA. Proc Natl Acad Sci U S A 98(8), 4449-54.
Hofacre, A., and Fan, H. (2004). Multiple domains of the Jaagsiekte sheep retrovirus envelope protein are required for transformation of rodent fibroblasts. J Virol 78(19), 10479-89.
Kuznetsov, Y. G., Low, A., Fan, H., and McPherson, A. (2004). Atomic force microscopy investigation of wild-type Moloney murine leukemia virus particles and virus particles lacking the envelope protein. Virology 323(2), 189-96.
Maeda, N., Fu, W., Ortin, A., de las Heras, M., and Fan, H. (2005). Roles of the Ras-MEK-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt-mTOR pathways in Jaagsiekte sheep retrovirus-induced transformation of rodent fibroblast and epithelial cell lines. J Virol 79(7), 4440-50.
McGee-Estrada, K., and Fan, H. (2006). In vivo and in vitro analysis of factor binding sites in Jaagsiekte sheep retrovirus long terminal repeat enhancer sequences: roles of HNF-3, NF-I, and C/EBP for activity in lung epithelial cells. J Virol 80(1), 332-41.
Low, A., Datta, S., Kuznetsov, Y., Jahid, S., Kothari, N., McPherson, A., and Fan, H. (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(8), 3685-92. |
