Nearly half of the more than two dozen known mammalian oncogenes encode molecules containing recognizable protein typrosine kinase domains. The precise functions of these kinases are in no cases known, however some serve as specific receptors for growth factors and it is likely that all will participate in the regulation of cell proliferation. The lymphocyte-specific protein tyrosine kinase gene lck is rearranged and overexpressed in a subset of lymphoid malignancies and resides at a site of frequent chromosmal abnormalities in human lymphoid tumors (1p32-35). Thus the lck gene is implicated in the pathogenesis of lymphoid malignancy and hence in the control of lymphocyte proliferation. This proposal seeks support for the detailed characterization of the lck gene in man and mouse and the identification of regulatory regions controlling its expression. To investigate the function of the lck kinase, altered versions of the lck gene will be reintroduced into cells and transgenic mice under the control of heterologous regulatory elements. In addition, other members of the lck gene family, defined by structural homology and similar expression patterns, will be examined in detail. The long-range goal of these experiments is the molecular dissection of growth regulatory pathways within the lymphoid cell linage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045682-02
Application #
3188870
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1987-09-30
Project End
1990-09-29
Budget Start
1988-09-30
Budget End
1989-09-29
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Norment, A M; Forbush, K A; Nguyen, N et al. (1997) Replacement of pre-T cell receptor signaling functions by the CD4 coreceptor. J Exp Med 185:121-30
Perlmutter, R M; Alberola-Ila, J (1996) The use of dominant-negative mutations to elucidate signal transduction pathways in lymphocytes. Curr Opin Immunol 8:285-90
Hashimoto, K; Sohn, S J; Levin, S D et al. (1996) Requirement for p56lck tyrosine kinase activation in T cell receptor-mediated thymic selection. J Exp Med 184:931-43
Anderson, S J; Perlmutter, R M (1995) A signaling pathway governing early thymocyte maturation. Immunol Today 16:99-105
Gross, J A; Appleby, M W; Chien, S et al. (1995) Control of lymphopoiesis by p50csk, a regulatory protein tyrosine kinase. J Exp Med 181:463-73
Wildin, R S; Wang, H U; Forbush, K A et al. (1995) Functional dissection of the murine lck distal promoter. J Immunol 155:1286-95
Kerner, J D; Appleby, M W; Mohr, R N et al. (1995) Impaired expansion of mouse B cell progenitors lacking Btk. Immunity 3:301-12
Appleby, M W; Kerner, J D; Chien, S et al. (1995) Involvement of p59fynT in interleukin-5 receptor signaling. J Exp Med 182:811-20
Perlmutter, R M (1993) Molecular dissection of lymphocyte signal transduction pathways. Pediatr Res 33:S9-13;discussion S13-5
Levin, S D; Abraham, K M; Anderson, S J et al. (1993) The protein tyrosine kinase p56lck regulates thymocyte development independently of its interaction with CD4 and CD8 coreceptors [corrected] J Exp Med 178:245-55

Showing the most recent 10 out of 24 publications