Regulation of mouse SP-B gene promoter by AP-1 family members.
The regulatory role of activator protein-1 (AP-1) family members in mouse surfactant protein (SP) B (mSP-B) promoter function was assessed in the mouse lung epithelial cell line MLE-15. Expression of recombinant Jun B and c-Jun inhibited mSP-B promoter activity by 50-75%. Although c-Fos expression did not alter mSP-B transcription, Jun D enhanced mSP-B promoter activity and reversed inhibition of mSP-B by c-Jun or Jun B. A proximal AP-1 binding site (-18 to -10 bp) was identified that overlaps a thyroid transcription factor-1 binding site. Mutation of this proximal AP-1 site blocked both Jun B inhibition and Jun D enhancement and partially blocked c-Jun inhibition of promoter activity. Promoter deletion mutants were used to identify additional sequences mediating the inhibitory effects of c-Jun in the distal region from -397 to -253 bp. The AP-1 element in this distal site (-370 to -364 bp) is part of a composite binding site wherein AP-1, cAMP response element binding protein, thyroid transcription factor-1, and nuclear factor I interact. Point mutation of the distal AP-1 binding site partially blocked c-Jun-mediated inhibition of the SP-B promoter. Both stimulatory (Jun D) and inhibitory (c-Jun/Jun B) effects of AP-1 family members on mSP-B promoter activity are mediated by distinct cis-acting elements in the mSP-B 5'-flanking region.
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
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Z
Sever-Chroneos
C J
CJ
Bachurski
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C
Yan
J A
JA
Whitsett
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011510:Proteolipids / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology; D011663:Pulmonary Surfactants / Q000235:genetics*; D000074482:Thyroid Nuclear Factor 1; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D011510:Proteolipids; D016755:Proto-Oncogene Proteins c-jun; D011663:Pulmonary Surfactants; D000074482:Thyroid Nuclear Factor 1; D018808:Transcription Factor AP-1; D014157:Transcription Factors