Lung cancer is the leading cause of cancer mortality in the United States. Bronchiolo-alveolar carcinoma (BAC) accounts for as much as 25 percent of lung cancer; the incidence of BAC has been increasing, and it is not etiologically linked to tobacco smoke. Thus, there is need for research in BAG. Sheep provide a unique model for BAC: ovine pulmonary carcinoma (OPC) that is caused by an exogenous retrovirus, jaagsiekte sheep retrovirus (JSRV). Recently, we isolated an infectious and oncogenic molecular clone of JSRV. The mechanism by which JSRV causes OPC is of great interest. In preliminary experiments, we have found that JSRV contains direct transforming activity, as measured by DNA transfection assays in murine NIH3T3 cells. The transforming activity has been localized to the JSRV env gene. Other investigators have mapped the JSRV cell receptor to region of human chromosome 3p21.3, an area that shows loss of heterozygosity (LOH) in human tumors, including lung cancer. This raises the possibility that JSRV Env protein may cause oncogenic transformation by binding to, and interfering with, the function of a tumor suppressor gene. In the proposed experiments, we will explore the mechanism of oncogenic transformation induced by JSRV env. Specifically, we will: 1) Identify the region of JSRV Env protein responsible for transformation; 2) Identify the cellular protein(s) that interact with the critical region of Env; 3) Examine the role of Env protein in oncogenesis in vivo and develop transgenic mouse models for the disease; and 4) Study the mechanism of JSRV env-induced transformation. These experiments will give new insights into oncogenesis by JSRV (which is an important veterinary disease in high endemic regions), and they may shed light on the mechanism of BAG oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094188-05
Application #
7013152
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2002-02-15
Project End
2007-07-24
Budget Start
2006-02-01
Budget End
2007-07-24
Support Year
5
Fiscal Year
2006
Total Cost
$303,808
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Hsu, Tom; Phung, An; Choe, Kevin et al. (2015) Role for a Zinc Finger Protein (Zfp111) in Transformation of 208F Rat Fibroblasts by Jaagsiekte Sheep Retrovirus Envelope Protein. J Virol 89:10453-66
Nitta, Takayuki; Ha, Dat; Galvez, Felipe et al. (2015) Human and murine APOBEC3s restrict replication of koala retrovirus by different mechanisms. Retrovirology 12:68
Stavrou, Spyridon; Nitta, Takayuki; Kotla, Swathi et al. (2013) Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex. Proc Natl Acad Sci U S A 110:9078-83
Hull, Stacey; Lim, Joohyun; Hamil, Alexander et al. (2012) Analysis of jaagsiekte sheep retrovirus (JSRV) envelope protein domains in transformation. Virus Genes 45:508-17
Nitta, Takayuki; Lee, Sangouk; Ha, Dat et al. (2012) Moloney murine leukemia virus glyco-gag facilitates xenotropic murine leukemia virus-related virus replication through human APOBEC3-independent mechanisms. Retrovirology 9:58
Nitta, Takayuki; Tam, Raymond; Kim, Jung Woo et al. (2011) The cellular protein La functions in enhancement of virus release through lipid rafts facilitated by murine leukemia virus glycosylated Gag. MBio 2:e00341-10
Johnson, Chassidy; Fan, Hung (2011) Three-dimensional culture of an ovine pulmonary adenocarcinoma-derived cell line results in re-expression of surfactant proteins and Jaagsiekte sheep retrovirus. Virology 414:91-6
Johnson, Chassidy; Jahid, Sohail; Voelker, Dennis R et al. (2011) Enhanced proliferation of primary rat type II pneumocytes by Jaagsiekte sheep retrovirus envelope protein. Virology 412:349-56
Hofacre, Andrew; Fan, Hung (2010) Jaagsiekte sheep retrovirus biology and oncogenesis. Viruses 2:2618-48
Nitta, Takayuki; Kuznetsov, Yurii; McPherson, Alexander et al. (2010) Murine leukemia virus glycosylated Gag (gPr80gag) facilitates interferon-sensitive virus release through lipid rafts. Proc Natl Acad Sci U S A 107:1190-5

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