This application proposes to study the regulation of Rev shuttling and localization. We seek to determine how the rates of import and export of Rev are modulated by the cellular environment. We will gain insights into this process by seeking to understand why a single Rev NES functions inefficiently and why the nuclear localization of Rev is sensitive to the inhibition of transcription and exposure to oxidative stress. Preliminary studies show that Vpr can shuttle between the nucleus and cytoplasm. This observation indicates that Vpr is Rev-like because it contains both a nuclear import and a nuclear export signal. This proposal will compare the shuttling of Vpr to that of Rev and determine if their export is mediated by the same cellular factors. The studies will also identify and characterize the NES in Vpr. The long-term objective is to understand the molecular details of HIV Rev action and Vpr shuttling. Defining the details of the regulation of Rev import and export and the export of Vpr will lead to a better understanding of the interactions between these proteins and endogenous transport pathways. This basic knowledge may lay the groundwork for novel therapeutic approaches targeting Rev function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI035477-06A1
Application #
6021936
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Plaeger, Susan F
Project Start
1994-08-01
Project End
2002-05-31
Budget Start
1999-06-15
Budget End
2000-05-31
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Popa, Ileana; Harris, Matthew E; Donello, John E et al. (2002) CRM1-dependent function of a cis-acting RNA export element. Mol Cell Biol 22:2057-67
Audit, M; Dejardin, J; Hohl, B et al. (1999) Introduction of a cis-acting mutation in the capsid-coding gene of moloney murine leukemia virus extends its leukemogenic properties. J Virol 73:10472-9
Stommel, J M; Marchenko, N D; Jimenez, G S et al. (1999) A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J 18:1660-72
Hope, T J (1999) The ins and outs of HIV Rev. Arch Biochem Biophys 365:186-91
Tang, H; McDonald, D; Middlesworth, T et al. (1999) The carboxyl terminus of RNA helicase A contains a bidirectional nuclear transport domain. Mol Cell Biol 19:3540-50
Johnson, C; Van Antwerp, D; Hope, T J (1999) An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. EMBO J 18:6682-93
Harris, M E; Gontarek, R R; Derse, D et al. (1998) Differential requirements for alternative splicing and nuclear export functions of equine infectious anemia virus Rev protein. Mol Cell Biol 18:3889-99
Otero, G C; Harris, M E; Donello, J E et al. (1998) Leptomycin B inhibits equine infectious anemia virus Rev and feline immunodeficiency virus rev function but not the function of the hepatitis B virus posttranscriptional regulatory element. J Virol 72:7593-7
Belshan, M; Harris, M E; Shoemaker, A E et al. (1998) Biological characterization of Rev variation in equine infectious anemia virus. J Virol 72:4421-6
Smith 3rd, G J; Donello, J E; Luck, R et al. (1998) The hepatitis B virus post-transcriptional regulatory element contains two conserved RNA stem-loops which are required for function. Nucleic Acids Res 26:4818-27

Showing the most recent 10 out of 14 publications