Synergistic transactivation of the differentiation-dependent lung gene Clara cell secretory protein (secretoglobin 1a1) by the basic region leucine zipper factor CCAAT/enhancer-binding protein alpha and the homeodomain factor Nkx2.1/thyroid transcription factor-1.
The basic region-leucine zipper transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) and the homeodomain transcription factor Nkx2.1/thyroid transcription factor-1 are essential for normal lung morphogenesis. Nkx2.1 is expressed from the onset of lung development, whereas C/EBPalpha expression is turned on at later stages. The expression of C/EBPalpha correlates to the appearance of lung-specific proteins with differentiation-dependent expression patterns, such as the Clara cell secretory protein (secretoglobin 1a1 (Scgb1a1), CCSP). In this study, we demonstrate synergistic transactivation by C/EBPalpha and Nkx2.1 in the regulation of the CCSP gene. We show that the synergistic activity of C/EBPalpha and Nkx2.1 originates from cis-acting elements in the proximal promoter of CCSP and that the synergism is dependent on NH(2)-terminal transactivation domains of C/EBPalpha and Nkx2.1. Our results suggest that the cooperation of C/EBPalpha and Nkx2.1 is a major determinant for the high level, lung epithelial-specific expression of CCSP during the later stages of lung development and in the adult lung.
Cassel
Tobias N
TN
Department of Medical Nutrition, Karolinska Institutet, Novum, SE-141 86 Huddinge, Sweden.
Berg
Tove
T
Suske
Guntram
G
Nord
Magnus
M
D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics*; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000196:embryology / Q000502:physiology*; D051379:Mice; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D014598:Uteroglobin
D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers; C000614414:Nkx2-1 protein, mouse; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; C556390:Scgb1a1 protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D014598:Uteroglobin