Abstract
Thyroid transcription factor-1 (TTF-1/Nkx-2.1) is required for formation of the lung and differentiation of peripheral respiratory epithelial cells. TTF-1 activates transcription of target genes, including the surfactant proteins critical for lung function. A recently identified protein TAZ (transcriptional co-activator with PDZ-binding motif) contains a WW domain and a COOH-terminal PDZ-binding motif that are proposed to mediate its interactions with various transcriptional proteins. To determine the role of TAZ in the regulation of gene expression in the lung, the sites of TAZ expression and the role of TAZ in the regulation of respiratory epithelial gene expression were assessed. TAZ mRNA was detected in immortalized mouse lung epithelial cells, primary isolates of mouse alveolar type II epithelial cells, and epithelial cells of fetal lung. Sites of TAZ mRNA and protein overlapped with those of TTF-1 and surfactant protein C (SP-C) in the respiratory epithelial cells of the mouse lung. In the presence of TTF-1, TAZ synergistically activated the expression of mouse SP-C-luciferase reporter constructs. Mammalian two-hybrid assays and pull-down experiments demonstrated that the TAZ directly interacted with TTF-1. Further, deletion analysis demonstrated that TAZ binds to the NH(2)-terminal domain of TTF-1. TAZ binds to TTF-1, increasing the transcriptional activity of TTF-1 on the SP-C promoter. Developmental and cell-selective regulation of TAZ provides a mechanism by which the activity of TTF-1 on target genes is modulated.
Highlights
Thyroid transcription factor-1 (TTF-1,1 termed T-EBP/ Nkx2.1) is a member of the Nkx-2 class of homeodomain-containing transcription factors [1, 2] that is selectively expressed in the developing thyroid, respiratory epithelium, and restricted areas of the developing brain [3,4,5]
TAZ Is Expressed in Respiratory Epithelial Cells of the Developing Lung—Since their structures indicate the potential for interactions between TAZ and TTF-1 in the regulation of surfactant gene expression, it was relevant to test whether the two proteins co-exist in respiratory epithelial cells
We demonstrated that TAZ acts as a transcriptional co-activator of TTF-1, enhancing its transcriptional activity on the mouse surfactant protein C promoter (Fig. 6)
Summary
Thyroid transcription factor-1 (TTF-1,1 termed T-EBP/ Nkx2.1) is a member of the Nkx-2 class of homeodomain-containing transcription factors [1, 2] that is selectively expressed in the developing thyroid, respiratory epithelium, and restricted areas of the developing brain [3,4,5]. TAZ physically interacted with TTF-1 through WW domain binding to an NH2-terminal LPPY motif of TTF-1 to regulate TTF-1mediated activation of the gene encoding SP-C (sftp-c) in respiratory epithelial cells. TAZ mRNA was detected at relatively high levels in purified mouse alveolar type II cells (Fig. 1B), which are known to express TTF-1 and surfactant proteins [7, 8, 24].
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