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Papers In Press, published online ahead of print January 2, 2007
Medicine (Hematology/Oncology), Northwestern University Medical School and the Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611
Corresponding Author: e-eklund{at}northwestern.edu
Neurofibromin 1 (Nf1) is a Ras-GAP protein which regulates cytokine-induced proliferation of myeloid cells. In previous studies, we found that the interferon consensus sequence binding protein (ICSBP; also referred to as interferon regulatory factor 8) activates transcription of the gene encoding Nf1 (the NF1-gene) in differentiating myeloid cells. We also found that NF1-activation requires cytokine-stimulated phosphorylation of a conserved tyrosine residue in the IRF-domain of ICSBP/IRF8. In the current studies, we find that ICSBP/IRF8 cooperates with PU.1 and interferon regulatory factor 2 (IRF2) to activate a composite ets/IRF cis element in the NF1-promoter. We find that PU.1 binds directly to the NF1-cis element and DNA-bound PU.1 interacts with IRF2; recruiting IRF2 to the cis element. This interaction requires cytokine-induced phosphorylation of specific serine residues in the PU.1 PEST domain and of a conserved tyrosine residue in the IRF-domain of IRF2. We find that ICSBP/IRF8-interaction with the NF1-cis element requires pre-binding of PU.1 and IRF2. The conserved IRF-domain tyrosine in ICSBP/IRF8 is required for interaction with the DNA-bound PU.1-IRF2 hetero dimer. NF1-deficiency in myeloid progenitor cells results in cytokine hypersensitivity and myeloproliferation. Therefore, these studies identify a target-gene for the previously observed tumor-suppressor effect of PU.1. Additionally, these studies identify a tumor-suppressor function for the “oncogenic” transcription factor, IRF2.
J. Biol. Chem, 10.1074/jbc.M607760200
Submitted on August 14, 2006
Revised on December 26, 2006
Accepted on January 2, 2007
PU.1, interferon regulatory factor 2 (IRF2) and the interferon consensus sequence binding protein (ICSBP/IRF8) cooperate to activate NF1-transcription in differentiating myeloid cells
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