Disease relevance of TITF1

• Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate [1].
• UGRP1 is a downstream target gene for homeodomain transcription factor T/EBP/NKX2.1, which is predominantly expressed in lung epithelial cells, and may play an anti-inflammatory role in lung inflammation [2].
• Variable expression of keratins and nearly uniform lack of thyroid transcription factor 1 in thyroid anaplastic carcinoma [3].
• RESULTS: TSHR, TTF-1 and TRbeta1 levels were significantly lower in oncocytic tumours than in papillary carcinomas, as a result of specific biological changes in oncocytic tumours [4].
• Since a positive immunostaining for TTF-1 in cystic lesions of the neck was not only found in metastases of PTC, but also in non-malignant branchiogenic cysts, additional investigations, e.g. an immunostaining for TG, should be added in difficult cases [5].
• These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model [6].
• This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure [7].

Psychiatry related information on TITF1

• PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations [1].
• CONCLUSION: TITF-1 gene mutations should be considered in paediatric and adult patients with unexplained (combinations of) chorea, mental retardation, primary hypothyroidism, and chronic lung disease [8].
• In this study, a potential role for TTF-1 in the regulation of feeding behavior was identified [9].
• Food deprivation for two days markedly increased the hypothalamic levels of TTF-1 mRNA and protein [9].

High impact information on TITF1

• Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure [10].
• The first of these hypotheses is apparently supported by the fact the nonmetabolized amino acids, especially the L-leucine analogue b(-)2-amino-bicyclo[2,2,1]heptane-2-carbocyclic acid (BCH), stimulate insulin release [11].
• A clone of hybrid myelomas (NK2), secreting a mouse monoclonal antibody to human leukocyte interferon, has been isolated [12].
• Here, we report that t(2;3)(q13;p25), a translocation identified in a subset of human thyroid follicular carcinomas, results in fusion of the DNA binding domains of the thyroid transcription factor PAX8 to domains A to F of the peroxisome proliferator-activated receptor (PPAR) gamma1 [13].
• We present data confirming that the NK1 specificity depended on Lys80 (and not on Asn77); however recognition of NK2 ligands by NK cells was also controlled by the amino acid at position 80 (Asn), and mutation of Ser77 had no effect [14].

Chemical compound and disease context of TITF1

• A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa [15].
• To test this hypothesis, androgen-primed benign hyperplastic (BHC) and malignant tumorigenic (MTC) cells derived from the Lobund-Wistar rat model of autochthonous prostate adenocarcinoma were incubated with (14)C-AA [16].
• BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose-dependent manner [17].
• Using hexachlorocyclohexane (BHC) as a model histopathological, histoenzymological, biochemical, and electrophoretic studies were undertaken to find out certain parameters for early diagnosis of liver cancer [18].
• Toxicity and bioconcentration of BHC and lindane in selected estuarine animals [19].

Biological context of TITF1

• The transcription factor thyroid transcription factor-1 (TTF-1) is a homeodomain-containing protein that belongs to the NK2 family of genes involved in organogenesis [20].
• A -199-bp promoter construct showed the greatest suppression by IFN gamma whereas a -177-bp construct, in which the TTF-1 binding site was deleted, showed less suppressibility [21].
• The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay [22].
• Our results describe the first dominant negative missense mutation in a paired domain and provide evidence for a crucial role of the p300 coactivator in mediating the functional synergism between PAX8 and TTF-1 in thyroid-specific gene expression [23].
• Conclusion: These results are concordant with the phenotype of the two sisters studied and demonstrate a differential role for TTF1 in the different tissues in which it is expressed [24].

Anatomical context of TITF1

• PAX8 and TITF1 were first expressed in the median thyroid primordium [1].
• TITF1 was expressed in the ventral forebrain and lung [1].
• A reporter gene, containing a 202 bp fragment from the human Tg 5'-flanking region including the promoter sequence and the transcriptional start site, and expression vectors containing the cDNAs for human TTF-1 and Pax8 were used in cotransfection experiments, in the non-thyroidal cell lines COS-7 and HeLa [25].
• Thyroid transcription factor-1 in orbital adipose tissues: potential role in orbital thyrotropin receptor expression [26].
• One of the ten branchial cleft cysts stained for TTF-1, while all cases were negative for TG [5].

Associations of TITF1 with chemical compounds

• Retinoic acid stimulation of the human surfactant protein B promoter is thyroid transcription factor 1 site-dependent [27].
• Major histocompatibility complex (MHC) class I gene expression, which is also regulated by TTF-1 and Pax-8 in the thyroid, is simultaneously decreased; this maintains self tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation [28].
• HEX, PAX-8 and TTF-1 gene expression in human thyroid tissues: a comparative analysis with other genes involved in iodide metabolism [29].
• Addition of vitamin E normalized the levels of the three transcripts, while vitamin A normalized only those of TTF-1 and SP-B mRNA [30].
• Sequence analysis of the TITF1 gene in these patients revealed the presence of a heterozygous C > T substitution at nucleotide 745, leading to the replacement of a glutamine at position 249 for a premature stop codon [31].

Physical interactions of TITF1

• Calreticulin binds to the TTF-1 homeodomain and promotes its folding, suggesting that the mechanism involved in stimulation of transcriptional activity is an increase of the steady-state concentration of active TTF-1 protein in the cell [32].
• We suggest that a PKA-induced increase of TTF-1 phosphorylation and TBE binding activity mediates cyclic AMP-induced expression of the SP-A gene in lung type II cells [33].
• Hypophosphorylated TTF-1 is still able to bind its DNA consensus sequence within the thyroglobulin promoter, although a reporter construct whose expression is exclusively dependent on TTF-1 is not transactivated [34].
• The TTF-1/TAP26 complex differentially modulates surfactant protein-B (SP-B) and -C (SP-C) promoters in lung cells [35].
• By electromobility shift assay we demonstrated that NKX3.1 preferentially binds the TAAGTA sequence rather than the binding site for Nkx2.1 (CAAGTG) or Msx1 (TAATTG) [36].
• 1 interacts physically and functionally with FOXA1 [37].

Regulatory relationships of TITF1

• Calreticulin enhances the transcriptional activity of thyroid transcription factor-1 by binding to its homeodomain [32].
• Like other surfactant protein genes, ABCA3 expression was induced by thyroid transcription factor-1 in vitro [38].
• In summary, TTF-1 interacts with distinct proximal (-80 to -110) and distal (-439 to -331) cis-acting elements than regulate lung epithelial cell-specific transcription of the human SP-B gene [39].
• Recently, a t(2;3)(q13;p25) rearrangement, which juxtaposes the thyroid transcription factor PAX8 to the peroxisome proliferator-activated receptor (PPAR) gamma1, was described in FTCs [40].
• NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells [41].

Other interactions of TITF1

• Importantly, RA stimulation of the hSP-B promoter depends on tissue-specific thyroid transcription factor (TTF-1) DNA-binding sites [27].
• In this study we show that calreticulin, a Ca2+-binding protein with chaperone activity, binds to thyroid transcription factor-1 (TTF-1), a homeodomain-containing protein implicated in the differentiation of lung and thyroid [32].
• The DNA binding of NKX2.1 to Sp-B promoter was reduced in response to TGF-beta treatment, although expression of Nkx2.1 was not affected [42].
• Using a mammalian two hybrid assay, we found physical and functional interactions between SMAD3 and both NKX2.1 and HNF-3 [42].
• Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity [23].

Analytical, diagnostic and therapeutic context of TITF1

• TTF-1 binding sites could be localized precisely by lectron mobility shift assay [25].
• Site-directed mutagenesis of three nucleotides in each binding element inhibited binding of TTF-1 to the two oligonucleotides [25].
• Mutations in titf1 coding region may be an extremely rare event, and was not detected in our small sample size or, alternatively, such a mutant might even be viable since TTF-1 plays an important role in lung, brain, and pituitary development [43].
• TTF-1 expression and sub-cellular localization were determined by immunohistochemistry in 62 thyroid carcinomas, 15 benign lesions, and 2 normal thyroids [44].
• In addition, expressions of mRNAs for TTF-1 and SP-A were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing [45].

References