HoxA10 represses transcription of the gene encoding p67phox in phagocytic cells.
p67(phox) and gp91(phox) are components of the phagocyte-specific respiratory burst oxidase that are encoded by the NCF2 and CYBB genes, respectively. These genes are transcribed exclusively in myeloid cells that have differentiated beyond the promyelocyte stage. In mature phagocytes, NCF2 and CYBB transcription continues until cell death and further increases in response to IFN-gamma and other inflammatory mediators. Because p67(phox) and gp91(phox) expression profiles are similar, we hypothesize that common transcription factors interact with homologous cis elements in the CYBB and NCF2 genes to coordinate transcription. Previously, we identified a negative CYBB promoter cis element that is repressed by the homeodomain transcription factor HoxA10. We found that transcriptional repression requires HoxA10-dependent recruitment of histone deacetylase activity to the CYBB cis element. In response to IFN-gamma, phosphorylation of two tyrosine residues in the HoxA10 homeodomain decreases binding to CYBB promoter, thereby abrogating HoxA10-mediated repression. In the current studies, we investigate the possibility that HoxA10 similarly represses NCF2 transcription. We identify a sequence in the NCF2 promoter that is homologous to the HoxA10-binding CYBB cis element. We find that this NCF2 promoter sequence functions as a negative cis element that is repressed by HoxA10 in a tyrosine phosphorylation and histone deacetylase-dependent manner. Our results suggest that cytokine-stimulated pathways regulate HoxA10-mediated repression of the CYBB and NCF2 genes in differentiating myeloid cells and in mature phagocytes during the inflammatory response. Because p67(phox) and gp91(phox) are rate-limiting components for respiratory burst activity, our studies may identify rational therapeutic targets to modulate free radical generation in pathological conditions.
Lindsey
Stephan
S
Feinberg School of Medicine and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
Zhu
Chunliu
C
Lu
Yu Feng
YF
Eklund
Elizabeth A
EA
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000502:physiology; D010586:Phagocytes / Q000502:physiology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
D004268:DNA-Binding Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C079789:neutrophil cytosol factor 67K; C069634:HOXA10 protein, human; D014443:Tyrosine