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J. Biol. Chem., Vol. 277, Issue 39, 36878-36888, September 27, 2002
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From the The homeodomain protein HoxA10 interacts with
negative cis elements to repress gene transcription in undifferentiated
myeloid cells. The CYBB and NCF2 genes, which
encode the gp91PHOX and p67PHOX proteins, are
two such HoxA10 target genes. During interferon
SHP1 Protein-tyrosine Phosphatase Regulates HoxA10 DNA
Binding and Transcriptional Repression Activity in Undifferentiated
Myeloid Cells*
§¶
,§¶,§¶,
Department of Medicine, Northwestern
University Medical School, Chicago, Illinois 60611, § The Robert H. Lurie Comprehensive Cancer Center of
Northwestern University, Chicago, Illinois 60611, and
¶ Chicago Lakeside Veterans Administration Hospital,
Chicago, Illinois 60611, the Birmingham
Veterans Administration Hospital, Birmingham, Alabama 35294, and
the ** Department of Medicine, University of Alabama at
Birmingham, Birmingham, Alabama 35294
-induced myeloid
differentiation, tyrosine phosphorylation decreases HoxA10 DNA binding
affinity and transcriptional repression. Therefore, decreased HoxA10
repression contributes to increased CYBB and NCF2 transcription in differentiating myeloid cells. The
current studies investigate modulation of HoxA10 repression activity
during myelopoiesis. We determine that phosphorylation of tyrosine
residues in the conserved homeodomain decreases HoxA10-DNA binding. We also determine that interaction of the homeodomain phosphotyrosine residues with an adjacent domain in the HoxA10 protein is necessary for
decreased DNA binding affinity. Since SHP1 protein-tyrosine phosphatase
antagonizes myeloid differentiation and decreases CYBB and
NCF2 transcription, we investigated the influence of SHP1-protein-tyrosine phosphatase (PTP) on HoxA10 tyrosine
phosphorylation. We find that SHP1-PTP activity increases HoxA10 target
gene repression in undifferentiated myeloid cells. Consistent with
this, SHP1-PTP interacts with HoxA10 and decreases homeodomain-tyrosine
phosphorylation. These investigations suggest that SHP1-PTP activity,
in undifferentiated myeloid cells, influences HoxA10 repression of
myeloid-specific genes. Therefore, increased HoxA10 repression of
myeloid gene transcription is a molecular mechanism for SHP1 inhibition
of myeloid differentiation.
*
This work was supported by the following grants (to
E. A. E.): a Veteran's Administration Merit Review, a
Translational Research Award from the Leukemia and Lymphoma Society of
America, and National Institutes of Health Grant CA95266.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: Dept. of Medicine,
Northwestern University Medical School, Olson Pavilion, Rm. 8527, 710 N. Fairbanks Ct., Chicago, IL. E-mail:
e-eklund@northwestern.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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