This application seeks to characterize critical steps in the proliferative signalling pathways activated by GM-CSF in related cytokines in primitive myeloid cells. At least some cases of myeloid leukemia likely result from over activity of such signal pathways. Identification of critical or unique steps in such cascades may allow development of pharmacologic interventions to specifically disrupt these pathways. The specific hypothesis of this application is that expression of the pim-1 gene project, a 33 kd serine/threonine kinase, is necessary for effective proliferative signalling through GM-CSF and related receptors. The applicant further hypothesizes that pim-1 expression serves as a specific indicator of activation of such pathways. The hypothesis will be investigated by constructing cell systems which allow for the over expression or blockade of pim-1 activity. Factor-dependent myeloid cell lines will be transfected with plasmid constructs or retroviral constructs to allow autonomous expression of the pim-1 gene product.These lines will then be examined for factor- independent growth, impaired differentiation, inhibition of apoptosis and homotypic aggregation. Similar cell lines will be created utilizing plasmids containing antisense pim-1 constructs to inhibit activity of the endogenous pim-1 gene. These cells will be studied for the responsiveness to GM-CSF and related cytokines and their propensity to differentiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045672-06
Application #
2091960
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1987-08-01
Project End
1997-02-28
Budget Start
1995-05-17
Budget End
1996-02-29
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yan, Bin; Zemskova, Marina; Holder, Sheldon et al. (2003) The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem 278:45358-67