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Originally published In Press as doi:10.1074/jbc.M103381200 on August 1, 2001

J. Biol. Chem., Vol. 276, Issue 41, 37868-37878, October 12, 2001
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SHP1 Protein-tyrosine Phosphatase Inhibits gp91PHOX and p67PHOX Expression by Inhibiting Interaction of PU.1, IRF1, Interferon Consensus Sequence-binding Protein, and CREB-binding Protein with Homologous Cis Elements in the CYBB and NCF2 Genes*

Bryan KautzDagger , Renu KakarDagger §, Ebenezer David§, and Elizabeth A. Eklund||

From the  Department of Medicine, Northwestern University Medical School and The Robert H. Lurie Comprehensive Cancer Center, Chicago Lakeside Veterans Administration Hospital, Chicago, Illinois 60611 and Dagger  Birmingham Veterans Administration Hospital and the § Department of Medicine, University of Alabama, Birmingham, Alabama 35209

The CYBB and NCF2 genes encode the phagocyte respiratory burst oxidase proteins, gp91PHOX and p67PHOX. Previously, we identified homologous CYBB and NCF2 cis elements that are necessary for lineage-specific transcription during late myeloid differentiation. We determined that these homologous cis elements are activated by PU.1, IRF1, interferon consensus sequence-binding protein (ICSBP), and the CREB-binding protein (CBP). Since expression of PU.1 and ICSBP is lineage-restricted, our investigations identified a mechanism of lineage-specific CYBB and NCF2 transcription. Since PU.1, IRF1, ICSBP, and CBP are expressed in undifferentiated myeloid cells, our investigations did not determine the mechanism of differentiation stage-specific CYBB and NCF2 transcription. In the current investigations, we determine that SHP1 protein-tyrosine phosphatase (SHP1-PTP) inhibits gp91PHOX and p67PHOX expression, in undifferentiated myeloid cell lines, by decreasing interaction of PU.1, IRF1, ICSBP, and CBP with the CYBB and NCF2 genes. We also determine that IRF1 and ICSBP are tyrosine-phosphorylated during interferon gamma  differentiation of myeloid cell lines, and we identify IRF1 and ICSBP tyrosine residues that are necessary for CYBB and NCF2 transcription. Therefore, these investigations identify a novel mechanism by which SHP1-PTP antagonizes myeloid differentiation and determine that tyrosine phosphorylation of IRF1 and ICSPB mediates stage-specific transcriptional activation in differentiating myeloid cells.

* This work was supported by a Veterans Affairs Merit Review and National Institutes of Health FIRST Award HL5400 (to E. A. E.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed. Tel.: 312-503-3206; Fax: 312-908-5717; E-mail: e-eklund@northwestern.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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