NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells

• Published in: Gene Vol. 327; no. 1; pp. 25 - 36
• Main Authors: Zhu, Nian Ling, Li, Changgong, Xiao, Jing, Minoo, Parviz
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 18-02-2004
• Subjects: Animals; Binding Sites - genetics; Bmp4 promoters; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - metabolism; Cell Line, Tumor; Development; DNA - genetics; DNA - metabolism; Electrophoretic Mobility Shift Assay; Embryo, Mammalian - metabolism; Epithelial Cells - metabolism; Gene Expression Regulation, Developmental; Gene regulation; HeLa Cells; Humans; In Situ Hybridization; Luciferases - genetics; Luciferases - metabolism; Lung - embryology; Lung - metabolism; Lung - pathology; Lung morphogenesis; Mice; Mutation; Nkx2.1; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Oligonucleotides - genetics; Oligonucleotides - metabolism; Promoter Regions, Genetic - genetics; Protein Binding; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Response Elements - genetics; Sequence Deletion; Signaling; Thyroid Nuclear Factor 1; Transcription factor; Transcription Factors - genetics; Transcription Factors - physiology; Transcription, Genetic - genetics; TTF-1; DTT; DMSO; Gene regulation; dNTP; Tera2EC; bp; hBmp4; DMEM; EMSA; kb; Development; TTF-1/Nkx2.1; Transcription factor; PBS; FGF; SpA; GATA; SpC; E15; TTF-1; T/EBP; Nkx2.1; BMP4; Lung morphogenesis; Signaling; ATP; HNF-3; PCR; Bmp4 promoters; E-CAD
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2003.11.013

Bone morphogenetic protein 4, BMP4, plays an important role in the development of various organs including the lungs. Little is known regarding the regulation of
Bmp4 gene expression in any organ. In the lung, indirect evidence indicates that NKX2.1, a homeodomain transcriptional factor with a demonstrated role in lung morphogenesis, may be a potential upstream regulator of
Bmp4 gene expression. In particular,
Bmp4 mRNA is reduced or absent in
Nkx2.1(−/−) lungs. The human
Bmp4 gene has been reported to include two regions of promoter activity in an embryonal carcinoma cell line, Tera2EC. The
hBmp4.1 promoter is located upstream of exon I, whereas the second promoter,
hBmp4.2, is localized within intron 1 and upstream of exon II. In the current study, we used a co-transfection assay in lung epithelial cells to examine the response of the two
hBmp4 promoters to transcriptional stimulation by NKX2.1. Two DNA sequences were identified on the
hBmp4.1 promoter that bind NKX2.1 and serve as functional cis-active NKX2.1-responsive elements. Similarly, NKX2.1 stimulated transcription from the
hBmp4.2 promoter through two consensus binding sites localized within 412 nucleotides from the site of transcriptional initiation. Thus, both
hBmp4 promoters include specific cis-active elements that bind to and mediate transcriptional regulation by NKX2.1. These findings bear functional implications regarding the regulation of a key signaling molecule by a homeodomain transcriptional regulator of lung epithelial morphogenesis.