Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung.
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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ABSTRACT: Well-standardized primary treatment and long-term management of differentiated thyroid carcinoma (DTC) include lowering or suppression of host thyrotropin (TSH) with exogenous L-thyroxine (T4). This treatment recognizes the trophic action of TSH on DTC cells. Suppression of endogenous TSH with T4 is continued in recurrent disease. However, T4 can induce proliferation of follicular and papillary thyroid carcinoma cell lines and of other human carcinoma cells. The proliferative mechanism is initiated at a cell surface receptor for T4 on integrin αvβ3, a receptor by which the hormone also inhibits p53-dependent apoptosis in tumor cells. In recurrent DTC with satisfactory suppression of endogenous TSH, we discuss here the possibility that the tumor is no longer TSH dependent and that T4 has become a critical growth factor for the cancer.Hormones & cancer. 10/2014; 6(1).
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ABSTRACT: Collectins, collagen-containing Ca2+ dependent C-type lectins and a class of secretory proteins including SP-A, SP-D and MBL, are integral to immunomodulation and innate immune defense. In the present study, we aimed to investigate their placental transcript synthesis, labor associated differential expression and localization at feto-maternal interface, and their functional implication in spontaneous labor. The study involved using feto-maternal interface (placental/decidual tissues) from two groups of healthy pregnant women at term (≥37 weeks of gestation), undergoing either elective C-section with no labor ('NLc' group, n = 5), or normal vaginal delivery with spontaneous labor ('SLv' group, n = 5). The immune function of SP-D, on term placental explants, was analyzed for cytokine profile using multiplexed cytokine array. SP-A, SP-D and MBL transcripts were observed in the term placenta. The 'SLv' group showed significant up-regulation of SP-D (p = 0.001), and down-regulation of SP-A (p = 0.005), transcripts and protein compared to the 'NLc' group. Significant increase in 43 kDa and 50 kDa SP-D forms in placental and decidual tissues was associated with the spontaneous labor (p<0.05). In addition, the MMP-9-cleaved form of SP-D (25 kDa) was significantly higher in the placentae of 'SLv' group compared to the 'NLc' group (p = 0.002). Labor associated cytokines IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α and MCP-1 showed significant increase (p<0.05) in a dose dependent manner in the placental explants treated with nSP-D and rhSP-D. In conclusion, the study emphasizes that SP-A and SP-D proteins associate with the spontaneous labor and SP-D plausibly contributes to the pro-inflammatory immune milieu of feto-maternal tissues.PLoS ONE 01/2014; 9(10):e108815. · 3.53 Impact Factor
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ABSTRACT: Nkx2 homeodomain transcription factors are involved in various developmental processes and cell specification: e.g. in mammals, NKX2-1 is essential for thyroid-specific gene expression and thyroid morphogenesis. Among Nkx2 proteins, information is still very limited for Nkx2-4. In the present study, we have identified three distinct cDNAs encoding Nkx2-4 isoforms (Nkx2-4a, -b, and -c) from the rainbow trout thyroid tissue, and characterized their transcriptional properties. The trout Nkx2-4 proteins were all predicted to conserve three characteristic domains: the tinman-like amino terminal decapeptide, the NK2 homeodomain, and the NK2-specific domain, and also share 75-89% amino acid similarity. It was shown by dual luciferase assay that Nkx2-4a and Nkx2-4b, but not Nkx2-4c, significantly activated transcription from a cotransfected rat thyroglobulin (TG) promoter. An electrophoretic mobility shift assay indicated that all the Nkx2-4 isoforms could bind to the TG promoter, implying that the faint transcriptional activity of Nkx2-4c might result from some critical amino acid substitution(s) outside the homeodomain. RT-PCR analysis revealed similar tissue distribution patterns for Nkx2-4a and Nkx2-4b mRNAs. Both mRNAs were expressed abundantly in the thyroid, and weakly in the testis. On the other hand, Nkx2-4c mRNA was detected in the ovary as well as in the thyroid. The expression sites of Nkx2-4c mRNA were localized, by in situ hybridization histochemistry, to the ovarian granulosa cells and to the thyroid follicular cells. The results suggest that in the rainbow trout, Nkx2-4a and Nkx2-4b might play a major role in TG gene transcription whereas Nkx2-4c might have some functions in the ovary as well as the thyroid.General and Comparative Endocrinology 07/2014; · 2.67 Impact Factor