A novel splice variant of the transcription factor Nrf1 interacts with the TNFalpha promoter and stimulates transcription.
Common signaling chains of various receptor families, despite some similarities, are able to provoke quite different cellular responses. This suggests that they are linked to different cascades and transcription factors, dependent on the context of the ligand binding moiety and the cell type. The ITAM (immunoreceptor tyrosine-based activation motif) containing gamma chain of the FcepsilonRI, FcgammaRI, FcgammaRIII and the T-cell receptor is one of these shared signaling molecules. Here, we show that in the context of the FcgammaRIII, the gamma chain activates the transcription factor Nrf1 or a closely related protein that specifically interacts with the extended kappa3 site in the TNFalpha promoter. A novel splice variant of Nrf1 with a 411 bp deletion of the serine-rich region, resulting in an overall structure reminiscent of the BTB and CNC homology (Bach) proteins, was isolated from the corresponding DC18 cells. In a gel shift analysis, this bacterially expressed splice variant binds to the TNFalpha promoter site after in vitro phosphorylation by casein kinase II (CKII). In addition, cotransfection studies demonstrate that this splice variant mediates induced transcription at the TNFalpha promoter after stimulation/activation in a heterologous system.
Prieschl
E E
EE
Department of Immunology, Novartis Research Institute, Brunner Strasse 59, A-1235 Vienna, Austria. eva.prieschl@pharma.novartis.com
Novotny
V
V
Csonga
R
R
Jaksche
D
D
Elbe-Bürger
A
A
Thumb
W
W
Auer
M
M
Stingl
G
G
Baumruker
T
T
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D047390:Casein Kinase II; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008407:Mast Cells; D051379:Mice; D008969:Molecular Sequence Data; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D017452:Receptors, IgG / Q000502:physiology; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C495633:NRF1 protein, human; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases