CYTOKINE SIGNALING AND ABL INDUCED TRANSFORMATION

  • Rothman, Paul (PI)

Project: Research project

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.
StatusFinished
Effective start/end date6/1/983/31/03

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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