GABP cooperates with c-Myb and C/EBP to activate the neutrophil elastase promoter.
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 GABP alpha, an ets factor, and GABP beta, a Notch-related protein. GABP alpha bound to the mNE ets site and, in turn, recruited GABP beta to form a transcriptionally active complex. GABP alpha 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/EBP alpha 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.
Nuchprayoon
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I
Division of Pediatric Oncology, The Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, MD, USA.
Simkevich
C P
CP
Luo
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M
Friedman
A D
AD
Rosmarin
A G
AG
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D047390:Casein Kinase II; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D004790:Enzyme Induction; D051268:GA-Binding Protein Transcription Factor; D006801:Humans; D019272:Leukocyte Elastase / Q000096:biosynthesis / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020598:Proto-Oncogene Proteins c-myb; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; C495656:Gabpa protein, mouse; C495658:Gabpb1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D014157:Transcription Factors; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D019272:Leukocyte Elastase