Abstract
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 gp91(PHOX) and p67(PHOX) proteins, are two such HoxA10 target genes. During interferon gamma-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.
Highlights
Myelopoiesis is characterized by differentiation stage-specific transcription of defined sets of genes, resulting in acquisition of the mature myeloid phenotype (1)
We demonstrated that IFN␥-induced differentiation of U937 myeloid cells results in HoxA10 tyrosine phosphorylation (Fig. 1A) (11), which is temporally associated with decreased HoxA10 DNA binding and increased CYBB and NCF2 transcription (11)
SHP1-PTP Activity Increases HoxA10 Transcriptional Repression in Undifferentiated U937 Cells—In previous investigations, we found that activity of SHP1 protein-tyrosine phosphatase decreases transcription of the CYBB and NCF2 genes in undifferentiated myeloid cells (17)
Summary
Myelopoiesis is characterized by differentiation stage-specific transcription of defined sets of genes, resulting in acquisition of the mature myeloid phenotype (1). Other transcription factors, such as PU.[1], interferon consensus sequence-binding protein (ICSBP),[1] and HoxA10, are involved in gene transcription throughout myelopoiesis but have distinct differentiation stage-specific functions. The homeodomain protein HoxA10 is functionally regulated by post-translational modification during myeloid differentiation. HoxA10 blocks differentiation by repressing transcription of myeloid-specific genes, such as the genes encoding the respiratory burst oxidase proteins gp91PHOX and p67PHOX (CYBB and NCF2 genes, respectively) (11). During cytokine-induced differentiation of myeloid cell lines, HoxA10 is tyrosine-phosphorylated, which decreases HoxA10 DNA binding affinity (11). These results suggest that HoxA10 tyrosine phosphorylation provides a mechanism for differentiation stage-specific HoxA10 function. This suggests the hypothesis that SHP1-PTP substrates include transcription factors involved in CYBB and NCF2 transcription
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