Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung

Boggaram, Vijayakumar

doi:10.1042/cs20080068

Cited by 168 publications

(167 citation statements)

References 89 publications

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“…CT imaging demonstrated a range of fi ndings from mild to diffuse ground-glass opacities, cysts, infi ltrates, of the lung and the expression of surfactant protein (SP)-B, SP-C, and ABCA3, and a large network of other proteins. 4 Haploinsuffi ciency for NKX2-1 due to either complete gene deletions or loss-of-function mutations results in brain-thyroid-lung syndrome (MIM 610978), with affected individuals having variable degrees of pulmonary disease, thyroid dysfunction, and neurologic abnormalities. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Neonatal RDS and chronic lung disease in older individuals have been reported in association with NKX2-1 mutations, but the pulmonary phenotype remains incompletely characterized, particularly in older children.…”

Section: Variability In Clinical Presentation and Coursementioning

confidence: 99%

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

Hamvas

Deterding

Wert

et al. 2013

Chest

168

143

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Thyroid transcription factor 1 (TTF-1), encoded by the gene NKX2-1 (Entrez gene identifi cation number 7080 ), is expressed in the thyroid gland, brain, and lung. In the lung, it is an early marker of lung differentiation and is important for structural development M utations in genes encoding surfactant protein-B ( SFTPB ), member A3 of the ATP-binding cassette family of transporters ( ABCA3 ), and surfactant protein-C ( SFTPC ) cause neonatal respiratory distress syndrome (RDS) or childhood interstitial and diffuse lung disease (ChILD). 1 Considerable overlap in the clinical and histologic features of the lung disease associated with these mutations exists, which are collectively referred to as surfactant dysfunction disorders. Children with fi ndings of surfactant dysfunction but without identifi able mutations in the SFTPB , SFTPC, or ABCA3 genes have been reported. 2,3 Background: Mutations in the gene encoding thyroid transcription factor, NKX2-1 , result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identifi ed individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. Methods: Retrospective and prospective approaches identifi ed infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available.

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Section: Variability In Clinical Presentation and Coursementioning

confidence: 99%

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

Hamvas

Deterding

Wert

et al. 2013

Chest

168

143

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“…TTF-1 promoter activity is maintained by the combined or cooperative actions of HNF-3, Sp1, Sp3, GATA-6 and HOXB3 transcription factors. 34 Transcriptional factors probably control restrictive expression of TTF-1 in normal organs.…”

Section: Restoration Of Ttf-1 By Epigenetic Modifiersmentioning

confidence: 99%

Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas

Kondo

Nakazawa

et al. 2009

Laboratory Investigation

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Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, is a homeodomain containing transcriptional factor identified in thyroid, lung and central nervous system. In the thyroid, TTF-1 is essential for thyroid organogenesis and governs thyroid functions by regulating various thyroid-specific genes. We previously demonstrated that most differentiated thyroid neoplasms, including follicular adenomas/carcinomas and papillary carcinomas, express TTF-1 at both protein and mRNA levels. However, certain subtypes of thyroid cancers have shown low or negative expression of TTF-1. The aim of our study was to investigate the function of epigenetic modification in dysregulation of TTF-1 in thyroid carcinoma cells. We evaluated the expression of TTF-1 in primary thyroid tissues (normal thyroid, papillary carcinoma and undifferentiated carcinoma) and in thyroid carcinoma cell lines using immunohistochemistry and RT-PCR. Methylation-specific PCR targeting CpG islands of TTF-1 and chromatin immunoprecipitation (ChIP) for histone H3 lysine 9 (H3-lys9) were applied to clarify the correlation of the TTF-1 expression profile and epigenetic status. We also explored whether epigenetic modifiers, including 5-aza-deoxycytidine, could restore TTF-1 expression in thyroid carcinoma cells. In our current study, immunohistochemistry and RT-PCR showed positive expression of TTF-1 in normal thyroids and papillary carcinomas. Meanwhile, most of the undifferentiated carcinomas and the cell lines lost TTF-1 expression. No methylation in the CpG of TTF-1 promoter was detected in normal thyroids or papillary carcinomas. In contrast, DNA methylation was identified in 60% of the undifferentiated carcinomas (6/10) and 50% of the cell lines (4/8). ChIP assay demonstrated that acetylation of H3-lys9 was positively correlated with TTF-1 expression in thyroid carcinoma cells. Finally, DNA demethylating agents could restore TTF-1 gene expression in the thyroid carcinoma cell lines. Our data suggest that epigenetics is involved with inactivation of TTF-1 in thyroid carcinomas, and provide a possible means of using TTF-1 as a target for differentiationinducing therapy through epigenetic modification. Thyroid cancer is the most common malignancy of the endocrine organs, and its incidence rate has steadily increased over the last decade. 1 More than 95% of thyroid carcinomas are derived from follicular cells having a spectrum of differentiation from comparatively indolent carcinomas, including follicular thyroid carcinoma and papillary thyroid carcinoma (PTC), to the most invasive and lethal human malignancy, undifferentiated (anaplastic) thyroid carcinoma (UTC). 1 This wide spectrum of progression has been closely linked with a pattern of cumulative genetic defects that correlate with tumor differentiation, metastatic potential and aggressiveness. 2 Of these, RET rearrangements (RET/PTCs) and activating somatic mutations in RAS and BRAF oncogenes are mutually exclusive and represent important genetic events in thyroid carcinogenesis. [2][3][4] In addit...

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Interdependent TTF1 - ErbB4 interactions are critical for surfactant protein-B homeostasis in primary mouse lung alveolar type II cells

Marten

Nielsen

Dammann

2015

J. Cell Commun. Signal.

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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.

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Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung

Cited by 168 publications

References 89 publications

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas

Interdependent TTF1 - ErbB4 interactions are critical for surfactant protein-B homeostasis in primary mouse lung alveolar type II cells

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