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J. Biol. Chem., Vol. 279, Issue 49, 50874-50885, December 3, 2004

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The Interferon Consensus Sequence-binding Protein Activates Transcription of the Gene Encoding Neurofibromin 1^*

Chunliu Zhu, Gurveen Saberwal, YuFeng Lu, Leonidas C. Platanias, and Elizabeth A. Eklund

From the Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University and Chicago Lakeside Veterans Affairs Hospital, Chicago, Illinois 60611

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 hypersen-sitivity." 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 hyper-sensitivity 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.

Received for publication, May 24, 2004 , and in revised form, September 2, 2004.

^* This work was supported by a Veterans Affairs Merit Review, a Translational Research Award from the Leukemia and Lymphoma Society of America, and National Institutes of Health Grants CA95266 and CA095266 (all to E. A. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: Feinberg School of Medicine, 710 North Fairbanks Court, Olson Pavilion Rm. 8524, Chicago, IL 60611. Tel.: 312-503-4625; Fax: 312-908-5717; E-mail: e-eklund{at}northwestern.edu.

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