Project Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 6/1/98 → 3/31/03 |
Funding
- National Cancer Institute: US$193,899.00
- National Cancer Institute: US$185,617.00
- National Cancer Institute: US$189,696.00
ASJC Scopus Subject Areas
- Cell Biology
- Cancer Research
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