We have previously shown that murine pre-B cell lines transformed with the Abelson murine leukemia virus (A-MuLV) exhibit constitutive, ligand independent, activation of the IL-4 and IL-7 JAK-STAT signaling pathways. This includes the activation of the Jak1 and Jak3 non- receptor tyrosine kinases and the STAT transcription factors which are normally activated by IL-4 and IL-7, namely Stat5 and Stat6. The constitutive activation of IL-4 and IL-7 signaling pathways has been observed in all pre-B cell lines transformed with the v-Abl oncoprotein. Using cells which contain a temperature sensitive mutant of v-Abl, we have shown that the kinase activity of v-Abl is required for the constitutive cytokine signaling in these cells. Because IL-7 is an essential growth factor for pre-B cells and IL-4 is a growth factor for many cells, we hypothesize that the ability of v-abl to activate these signaling pathways is related to its ability to transform pre-B cells. Our initial characterization of A-MuLV-transformed pre-B cells revealed that, in these cells, v-Abl can be immunoprecipitated with the Jak1 kinase. Our recent results, using recombinant proteins, have shown that v-Abl directly associates with Jak1. In addition, the ability of v-abl to activate transcription initiating from STAT reporter constructs is repressed by expression of a dominant negative mutant of Jak1. This result leads us to hypothesize that the interaction between the v-Abl and JAK proteins might be important both for the activation of cytokine signaling in these cells and, possibly, their transformed state. To address this question, we propose the following: 1)Analysis of the region(s) of v-Abl and the Jak kinases that interact, 2) To determine if v-Abl-Jak kinase interactions are required for transformation of pre-B cells, 3) To determine if v-abl can transform cells which lack a functional Jak1, Jak3, Stat6, Stat5, the gamma C receptor or the IL-r alpha chain, 4) Analysis of the relationship between the ability of v-Abl to signal via JAK kinases and its ability to activate other signaling pathways.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077862-05
Application #
6513224
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Cole, John S
Project Start
1998-06-01
Project End
2003-03-31
Budget Start
2002-06-18
Budget End
2003-03-31
Support Year
5
Fiscal Year
2002
Total Cost
$193,899
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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Limnander, Andre; Danial, Nika N; Rothman, Paul B (2004) v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells. Mol Cell 15:329-41
Kim, Han; Xu, Guo-Liang; Borczuk, Alain C et al. (2003) The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor. Am J Respir Cell Mol Biol 29:694-701
Oki, Shinji; Limnander, Andre; Danial, Nika N et al. (2002) Functional involvement of Akt signaling downstream of Jak1 in v-Abl-induced activation of hematopoietic cells. Blood 100:966-73
Banerjee, A; Rothman, P (1998) IL-7 reconstitutes multiple aspects of v-Abl-mediated signaling. J Immunol 161:4611-7