Abstract

Tyrosine protein kinases play a central role in the regulation of cell multiplication. This project is directed at understanding the function of the tyrosine protein kinase encoded by the lck proto-oncogene, p56lck. This regulatory molecule is of interest because it is expressed exclusively in lymphoid cells and because it is implicated in lymphomagenesis. The work has three parts. One is designed to define precisely the transforming potential of wild-type lck and of genetically-activated lck. This will be done by the infection of neo-natal mice and cultured lymphoid cells with retroviruses expressing p56lck. The identity of transformed cells will be determined by the analysis of surface markers. This should reveal the types of cells that this protein can transform. Additionally, the potential role of p56lck in human leukemia will be examined by characterization of the protein in leukemic cell lines. Second, the role of p56lck in normal lymphoid function will be examined. Agents that induce the dephosphorylation and activation of p56lck will be sought and their mode of action determined. Additionally, the effect of ectopic or excessive expression of p56lck on the function of hematopoietic cell lines will be examined by infection with retroviruses encoding p56lck and determination of the functional properties of the infected cells. From perturbations of function, it is hoped that the normal function of the protein can be inferred. Finally, because lck is expressed only in lymphoid cells, the structure and properties of the promoters and enhancers driving the expression of the gene are of considerable interest. These will be isolated by molecular cloning and the regions conferring specificity will be identified through the use of luciferase as a reporter gene.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042350-08
Application #
2090682
Study Section
Virology Study Section (VR)
Project Start
1986-04-01
Project End
1994-11-30
Budget Start
1993-05-28
Budget End
1994-11-30
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Schulte, Roberta J; Sefton, Bartholomew M (2003) Inhibition of the activity of SRC and Abl tyrosine protein kinases by the binding of the Wiskott-Aldrich syndrome protein. Biochemistry 42:9424-30
Kjellen, Peter; Amdjadi, Kambiz; Lund, Troy C et al. (2002) The herpesvirus saimiri tip484 and tip488 proteins both stimulate lck tyrosine protein kinase activity in vivo and in vitro. Virology 297:281-8
Chiang, G G; Sefton, B M (2001) Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J Biol Chem 276:23173-8
Chiang, G G; Sefton, B M (2000) Phosphorylation of a Src kinase at the autophosphorylation site in the absence of Src kinase activity. J Biol Chem 275:6055-8
Hartley, D A; Cooper, G M (2000) Direct binding and activation of STAT transcription factors by the herpesvirus saimiri protein tip. J Biol Chem 275:16925-32
Hartley, D A; Amdjadi, K; Hurley, T R et al. (2000) Activation of the Lck tyrosine protein kinase by the Herpesvirus saimiri tip protein involves two binding interactions. Virology 276:339-48
Amdjadi, K; Sefton, B M (2000) Ultraviolet light-induced stimulation of the JNK mitogen-activated protein kinase in the absence of src family tyrosine kinase activation. J Biol Chem 275:22520-5
Hartley, D A; Hurley, T R; Hardwick, J S et al. (1999) Activation of the lck tyrosine-protein kinase by the binding of the tip protein of herpesvirus saimiri in the absence of regulatory tyrosine phosphorylation. J Biol Chem 274:20056-9
Lund, T C; Coleman, C; Horvath, E et al. (1999) The Src-family kinase Lck can induce STAT3 phosphorylation and DNA binding activity. Cell Signal 11:789-96
Hardwick, J S; Sefton, B M (1997) The activated form of the Lck tyrosine protein kinase in cells exposed to hydrogen peroxide is phosphorylated at both Tyr-394 and Tyr-505. J Biol Chem 272:25429-32

Showing the most recent 10 out of 28 publications