Protein-tyrosine kinases have been broadly implicated in the control of both normal and neoplastic cell proliferation. Recently, the aberrant bcr- abl tyrosine kinase, a hallmark of chronic myelogenous leukemia, has been shown to cause a similar disease in transgenic mice. Our continuing work towards understanding the mechanisms whereby tyrosine phosphorylation regulates cell growth in general, and its role in chronic myelogenous leukemia in particular, has led us to focus attention on two cellular proteins which are excellent candidates for physiologically relevant substrates of tyrosine kinases: i) a 56-kDa protein constitutively tyrosine phosphorylated in all CML cells, but tyrosine phosphorylated in normal cells only in response to certain growth factors (e.g. EGF and CSF- 1): Using my 1G2-antibody to phosphotyrosine, we have already succeeded in purifying sufficient quantities of the 56-Da protein to develop anti- protein monoclonal antibodies, ii) a 62-kDa protein which physically associates with physiologically important proteins (e.g. GAP, abl, PLCgamma) containing regions homologous to the second (SH2) domain of src. Phorbol ester-induced terminal differentiation of CML-cell lines causes a physical association of the tyrosine-phosphorylated p62 protein with tyrosine phosphorylated rasGAP (the ras, GTPase-activating protein). This is associated with an increase in ras protein activity that appears to be necessary for the phorbol ester-induced differentiation. The proposed studies seek to further explore the biochemical and mechanistic roles of the p56 and p62 proteins in cell proliferation and differentiation. Specifically, we seek: i) to characterize the biochemical and cellular functions of these proteins; ii) to determine whether these proteins are structurally homologous to proteins with known functions; iii) to determine the effects of overexpressing normal and mutant p56 and p62 proteins in normal fibroblasts, growth-factor dependent hematopoietic cells, and in CML cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039235-07A1
Application #
3178038
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1992-03-06
Project End
1995-02-28
Budget Start
1992-03-06
Budget End
1993-02-28
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Roger Williams Hospital
Department
Type
DUNS #
City
Providence
State
RI
Country
United States
Zip Code
02908
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Frackelton Jr, A R; Kumar, P S; Kannan, B et al. (1993) Tyrosine phosphorylated proteins in chronic myelogenous leukemia. Leuk Lymphoma 11 Suppl 1:125-9
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