A novel activation function for NAB proteins in EGR-dependent transcription of the luteinizing hormone beta gene.
The EGR1/NGFI-A transcription factor directly activates the luteinizing hormone beta (LHbeta) subunit promoter, and female mice lacking EGR1 are infertile due to LHbeta deficiency. The NGFI-A-binding proteins NAB1 and NAB2 are corepressors of EGR1/NGFI-A and of the related proteins EGR2/Krox20 and EGR3. Here we report that at certain promoters, including LHbeta, NAB proteins display a novel ability to stimulate EGR-directed transcription. NAB coactivation requires the conserved NCD2 protein domain, previously implicated in NAB corepression, is strictly dependent upon EGR binding to the LHbeta proximal promoter and is independent of EGR activation domains. Furthermore, we report that NAB-activated promoters such as LHbeta contain EGR consensus sites that are fewer in number and lower in binding affinity than those found at NAB-repressed promoters such as basic fibroblast growth factor. Analysis of mutant and synthetic promoters confirms that both the strength and multiplicity of EGR-binding sites influence the transcriptional outcome of NAB recruitment. These results suggest a novel means by which EGR target genes could be differentially regulated in cells where EGR and NAB proteins are coexpressed.
Sevetson
B R
BR
Departments of Pathology and Internal Medicine, Division of Laboratory Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Svaren
J
J
Milbrandt
J
J
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005260:Female; D017874:Immediate-Early Proteins; D007986:Luteinizing Hormone / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; C491000:NAB2 protein, human; C490624:Nab1 protein, mouse; C099945:Nab2 protein, mouse; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D007986:Luteinizing Hormone