GABP Cooperates With c-Myb and C/EBP to Activate the Neutrophil Elastase Promoter

• Published in: Blood 1997-06, Vol.89 (12), p.4546-4554
• Main Authors: Nuchprayoon, Issarang, Simkevich, Carl P., Luo, Menglin, Friedman, Alan D., Rosmarin, Alan G.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Casein Kinase II; CCAAT-Enhancer-Binding Proteins; Dimerization; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - classification; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Enzyme Induction; Fundamental and applied biological sciences. Psychology; Fundamental immunology; GA-Binding Protein Transcription Factor; Humans; Immunobiology; Leukocyte Elastase - biosynthesis; Leukocyte Elastase - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Mice; Molecular Sequence Data; Monocytes, macrophages; Multigene Family; Myeloid cells: ontogeny, maturation, markers, receptors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Nuclear Proteins - physiology; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-myb; Regulatory Sequences, Nucleic Acid; Signal Transduction; Trans-Activators - physiology; Transcription Factors - chemistry; Transcription Factors - classification; Transcription Factors - genetics; Transcription Factors - physiology; Transcription, Genetic; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V89.12.4546

Neutrophil elastase (NE) is a serine protease that is transcriptionally regulated during early myeloid differentiation. The murine NE (mNE) promoter contains functionally important c-Myb, C/EBP, and ets binding sites. Deletion of the ets site reduced promoter activity by 90%. Although the ets transcription factor, PU.1, bound to this ets site, it only modestly activated the mNE promoter. Here, we show that a second transcription factor from myeloid cells — GABP — binds to the mNE ets site but strongly activates the mNE promoter. GABP is a heteromeric transcription factor complex that consists of GABPα, an ets factor, and GABPβ, a Notch-related protein. GABPα bound to the mNE ets site and, in turn, recruited GABPβ to form a transcriptionally active complex. GABPα and PU.1 competed with each other for binding to the mNE ets site. GABP increased the activity of the mNE promoter sevenfold in U937 myeloid cells. GABP cooperated with c-Myb and C/EBPα to activate the mNE promoter more than 85-fold in otherwise nonpermissive, nonhematopoietic NIH 3T3 cells. Thus, GABP binds to the crucial mNE promoter ets site and powerfully activates its expression alone and in cooperation with the transcription factors c-Myb and C/EBP.