The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1.
Deficiency of the interferon consensus sequence-binding protein (ICSBP) is associated with increased myeloid cell proliferation in response to hematopoietic cytokines. However, previously identified ICSBP target genes do not indicate a mechanism for this "cytokine hypersensitivity." In these studies, we identify the gene encoding neurofibromin 1 (Nf1) as an ICSBP target gene, by chromatin immunoprecipitation. Additionally, we find decreased Nf1 expression in bone marrow-derived myeloid cells from ICSBP-/- mice. Since Nf1 deficiency is also associated with cytokine hypersensitivity, our results suggested that NF1 is a functionally significant ICSBP target gene. Consistent with this, we find that the hypersensitivity of ICSBP-/- myeloid cells to granulocyte monocyte colony-stimulating factor (GM-CSF) is reversed by expression of the Nf1 GAP-related domain. We also find that treatment of ICSBP-deficient myeloid cells with monocyte colony-stimulating factor (M-CSF) results in sustained Ras activation, ERK phosphorylation, and proliferation associated with impaired Nf1 expression. These M-CSF effects are reversed by ICSBP expression in ICSBP-/- cells. Consistent with this, we find that ICSBP activates the NF1 promoter in myeloid cell line transfectants and identify an ICSBP-binding NF1 cis element. Therefore, the absence of ICSBP leads to Nf1 deficiency, impairing down-regulation of Ras activation by GM-CSF or M-CSF. These results suggest that one mechanism of increased myeloid proliferation, in ICSBP-deficient cells, is decreased NF1 gene transcription. This novel ICSBP function provides insight into regulation of myelopoiesis under normal conditions and in myeloproliferative disorders.
Zhu
Chunliu
C
Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University and Chicago Lakeside Veterans Affairs Hospital, Chicago, Illinois 60611, USA.
Saberwal
Gurveen
G
Lu
Yufeng
Y
Platanias
Leonidas C
LC
Eklund
Elizabeth A
EA
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D050835:Interferon Regulatory Factors; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D025542:Neurofibromin 1 / Q000737:chemistry* / Q000235:genetics*; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D020298:U937 Cells; D018631:ras Proteins / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
D016207:Cytokines; D018076:DNA, Complementary; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D016173:Macrophage Colony-Stimulating Factor; D048052:Mitogen-Activated Protein Kinase 3; D025542:Neurofibromin 1; D009841:Oligonucleotides; D012313:RNA; D012097:Repressor Proteins; D018631:ras Proteins; D000099185:Interferon Regulatory Factor-8