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.
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.
Kautz
B
B
Department of Medicine, Northwestern University Medical School and The Robert H. Lurie Comprehensive Cancer Center, Chicago Lakeside Veterans Administration Hospital, Chicago, Illinois 60611, USA.
Kakar
R
R
David
E
E
Eklund
E A
EA
D001483:Base Sequence; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic; D020298:U937 Cells
D017931:DNA Primers; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; C079789:neutrophil cytosol factor 67K; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases