Thyroid transcription factor-I (TTF-I/Nkx2.I/TITFI) gene regulation in the lung

Department of Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708-3154, USA.
Clinical Science (Impact Factor: 5.6). 02/2009; 116(1):27-35. DOI: 10.1042/CS20080068
Source: PubMed

ABSTRACT TTF-1 [thyroid transcription factor-1; also known as Nkx2.1, T/EBP (thyroid-specific-enhancer-binding protein) or TITF1] is a homeodomain-containing transcription factor essential for the morphogenesis and differentiation of the thyroid, lung and ventral forebrain. TTF-1 controls the expression of select genes in the thyroid, lung and the central nervous system. In the lung, TTF-1 controls the expression of surfactant proteins that are essential for lung stability and lung host defence. Human TTF-1 is encoded by a single gene located on chromosome 14 and is organized into two/three exons and one/two introns. Multiple transcription start sites and alternative splicing produce mRNAs with heterogeneity at the 5' end. The 3' end of the TTF-1 mRNA is characterized by a rather long untranslated region. The amino acid sequences of TTF-1 from human, rat, mouse and other species are very similar, indicating a high degree of sequence conservation. TTF-1 promoter activity is maintained by the combinatorial or co-operative actions of HNF-3 [hepatocyte nuclear factor-3; also known as FOXA (forkhead box A)], Sp (specificity protein) 1, Sp3, GATA-6 and HOXB3 (homeobox B3) transcription factors. There is limited information on the regulation of TTF-1 gene expression by hormones, cytokines and other biological agents. Glucocorticoids, cAMP and TGF-beta (transforming growth factor-beta) have stimulatory effects on TTF-1 expression, whereas TNF-alpha (tumour necrosis factor-alpha) and ceramide have inhibitory effects on TTF-1 DNA-binding activity in lung cells. Haplo-insufficiency of TTF-1 in humans causes hypothyroidism, respiratory dysfunction and recurring pulmonary infections, underlining the importance of optimal TTF-1 levels for the maintenance of thyroid and lung function. Recent studies have implicated TTF-1 as a lineage-specific proto-oncogene for lung cancer.

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    • "ErbB4 is known to be important for differentiation of ATII cells of the developing lung (Dammann 2003), the mammary gland, the nervous system, and the heart (Carpenter 2002). In the lung, both TTF-1 and ErbB4 protein have important roles in promoting surfactant protein expression (Boggaram 2009; Zscheppang 2011). Our previous experiments in fetal murine ATII cells showed that there is an interaction between TTF-1 and ErbB4 (Zscheppang 2013). "
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    ABSTRACT: ErbB4 receptor and thyroid transcription factor (TTF)-1 are important modulators of fetal alveolar type II (ATII) cell development and injury. ErbB4 is an upstream regulator of TTF-1, promoting its expression in MLE-12 cells, an ATII cell line. Both proteins are known to promote surfactant protein-B gene (SftpB) and protein (SP-B) expression, but their feedback interactions on each other are not known. We hypothesized that TTF-1 expression has a feedback effect on ErbB4 expression in an in-vitro model of isolated mouse ATII cells. We tested this hypothesis by analyzing the effects of overexpressing HER4 and Nkx2.1, the genes of ErbB4 and TTF-1 on TTF-1 and ErbB4 protein expression, respectively, as well as SP-B protein expression in primary fetal mouse lung ATII cells. Transient ErbB4 protein overexpression upregulated TTF-1 protein expression in primary fetal ATII cells, similarly to results previously shown in MLE-12 cells. Transient TTF-1 protein overexpression down regulated ErbB4 protein expression in both cell types. TTF-1 protein was upregulated in primary transgenic ErbB4-depleted adult ATII cells, however SP-B protein expression in these adult transgenic ATII cells was not affected by the absence of ErbB4. The observation that TTF-1 is upregulated in fetal ATII cells by ErbB4 overexpression and also in ErbB4-deleted adult ATII cells suggests additional factors interact with ErbB4 to regulate TTF-1 levels. We conclude that the interdependency of TTF-1 and ErbB4 is important for surfactant protein levels. The interactive regulation of ErbB4 and TTF-1 needs further elucidation.
    Journal of Cell Communication and Signaling 07/2015; DOI:10.1007/s12079-015-0299-1
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    • "SPC is synthesized only in ATII cells and, therefore, is a specific marker for ATII cells [15]. The cell-type-specific expressions of SPB and SPC in Clara and ATII cells are required for lung respiratory function [16] [17]. Both gene expressions are regulated by thyroid transcription factor 1 (TTF-1) during lung development [18] [19] [20]. "
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    ABSTRACT: Stem cell therapy appears to be promising for restoring damaged or irreparable lung tissue. However, establishing a simple and reproducible protocol for preparing lung progenitor populations is difficult because the molecular basis for alveolar epithelial cell differentiation is not fully understood. We investigated an in vitro system to analyze the regulatory mechanisms of alveolus-specific gene expression using a human alveolar epithelial type II (ATII) cell line, A549. After cloning A549 subpopulations, each clone was classified into five groups according to cell morphology and marker gene expression. Two clones (B7 and H12) were further analyzed. Under serum-free culture conditions, surfactant protein C (SPC), an ATII marker, was upregulated in both H12 and B7. Aquaporin 5 (AQP5), an ATI marker, was upregulated in H12 and significantly induced in B7. When the RAS/MAPK pathway was inhibited, SPC and thyroid transcription factor-1 (TTF-1) expression levels were enhanced. After treatment with dexamethasone (DEX), 8-bromoadenosine 3'5'-cyclic monophosphate (8-Br-cAMP), 3-isobutyl-1-methylxanthine (IBMX), and keratinocyte growth factor (KGF), surfactant protein B and TTF-1 expression levels were enhanced. We found that A549-derived clones have plasticity in gene expression of alveolar epithelial differentiation markers and could be useful in studying ATII maintenance and differentiation.
    Stem cell International 07/2015; 2015:165867. DOI:10.1155/2015/165867 · 2.81 Impact Factor
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    • "Induction of transcription factors and growthfactor signaling in a temporal-spatial manner orchestrate migration and branching of the lung airway epithelium (Kimura and Deutsch, 2007). The signaling also plays a role in specification of cell fate once the airway has developed (Boggaram, 2009; Maeda et al., 2007; Rock and Hogan, 2011). While several reports have described the formation of spheroid structures when human or mouse airway epithelial cells are cultured in Matrigels, these models do not account for the epithelial–mesenchymal interactions (McQualter et al., 2010; Rock et al., 2009; Wu et al., 2011). "
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    ABSTRACT: While mouse models have contributed in our understanding of lung development, repair and regeneration, inherent differences between the murine and human airways requires the development of new models using human airway epithelial cells. In this study, we describe a three-dimensional model system using human bronchial epithelial cells (HBECs) cultured on reconstituted basement membrane. HBECs form complex budding and branching structures on reconstituted basement membrane when co-cultured with human lung fetal fibroblasts. These structures are reminiscent of the branching epithelia during lung development. The HBECs also retain markers indicative of epithelial cell types from both the central and distal airways suggesting their multipotent potential. In addition, we illustrate how the model can be utilized to understand respiratory diseases such as lung cancer. The 3D novel cell culture system recapitulates stromal-epithelial interactions in vitro that can be utilized to understand important aspects of lung development and diseases.
    Differentiation 05/2014; 87(3-4). DOI:10.1016/j.diff.2014.02.003 · 3.44 Impact Factor
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