JAK2 is necessary and sufficient for interferon-gamma-induced transcription of the gene encoding gp91PHOX.
During the inflammatory response, interferon-gamma (IFN-gamma) increases transcription of the gene encoding gp91PHOX, a respiratory burst oxidase component. This gene (referred to as the CYBB gene) is transcribed in phagocytic cells differentiated beyond the promyelocyte stage, and transcription continues until cell death. Previous investigations identified a positive regulatory element in the proximal CYBB promoter referred to as the hematopoiesis-associated factor 1 (HAF1)-cis element. This element is activated by a multiprotein complex, which includes the IFN consensus sequence-binding protein (ICSBP). Interaction of this complex with the HAF1-cis element requires ICSBP tyrosine phosphorylation, which is induced by IFN-gamma stimulation of phagocytic cells. Previous studies also identified a negative cis element in the CYBB promoter. This element is repressed by the homeodomain protein HoxA10. HoxA10 tyrosine phosphorylation, which occurs in response to IFN-gamma, decreases HoxA10 DNA binding and therefore repression of CYBB transcription. In these studies, we determine Janus tyrosine kinase 2 (JAK2) activation is necessary and sufficient for IFN-gamma-induced CYBB transcription in phagocytic cells and also for ICSBP and HoxA10 tyrosine phosphorylation. Consistent with these results, we find JAK2 activation is sufficient to induce ICSBP interaction with the HAF1 element and abolish HoxA10 binding to the CYBBrepressor element. Therefore, these findings provide direct demonstration of JAK2 dependence of IFN-gamma-induced CYBB transcription. In addition, these results identify a mechanism mediating this effect.
Kakar
Renu
R
The Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center, Northwestern University, and Jesse Brown VA Medical Center, Chicago, IL 60611, USA.
Kautz
Bryan
B
Eklund
Elizabeth A
EA
D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D006801:Humans; D047468:Immunoprecipitation; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology*; D007372:Interferons / Q000378:metabolism; D053614:Janus Kinase 2; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism; D020298:U937 Cells; D000099185:Interferon Regulatory Factor-8
D002701:Chloramphenicol; D004268:DNA-Binding Proteins; D049452:Green Fluorescent Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D007372:Interferons; D053614:Janus Kinase 2; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014443:Tyrosine; D000099185:Interferon Regulatory Factor-8; C026822:chloramphenicol 3-acetate; C069634:HOXA10 protein, human; C056558:CYBB protein, human; C507924:JAK2 protein, human