Clinical Science (2009) 116, 27–35 (Printed in Great Britain) doi:10.1042/CS20080068 27
REVIEW Thyroid transcription factor-1 (TTF-1/Nkx2.1/ TITF1) gene regulation in the lung
Vijay BOGGARAM Department of Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708-3154, U.S.A.
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-β (transforming growth factor-β)have stimulatory effects on TTF-1 expression, whereas TNF-α (tumour necrosis factor-α) 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.
INTRODUCTION ofthebrain[1].Homeodomain-containingtranscriptional factors play key roles in the control of embryonic devel- TTF-1 [thyroid transcription factor-1; also known as opment and differentiation [2,3]. A homeobox is a Nkx2.1, T/EBP (thyroid-specific-enhancer-binding pro- 180 bp DNA sequence motif encoding a protein domain tein) or TITF1], a member of the homeodomain-contain- that can bind the DNA in a sequence-specific manner. ing transcription factor family, activates the expression of Homeodomain-containing proteins control the tran- select genes in the thyroid, lung and restricted regions scriptional activation of target genes by binding to specific
Key words: inflammation, lung cancer, morphogenesis, promoter regulation, surfactant, thyroid transcription factor (TTF). Abbreviations: CCSP, Clara cell secretory protein; DEE, diesel engine emissions; EMT, epithelial–mesenchymal transition; FOX, forkhead box; HNF, hepatocyte nuclear factor; HOX, homeobox; IPF, idiopathic pulmonary fibrosis; MITF, microphthalmia- associated transcription factor; NSCLC, non-SCLC; PKA, protein kinase A; RNAi, RNA interference; SCC, squamous cell carcinoma; SCLC, small-cell lung carcinoma; SP, surfactant protein; T/EBP, thyroid-specific-enhancer-binding protein; TGF-β, transforming growth factor-β;TNF-α, tumour necrosis factor-α; TSH, thyroid-stimulating hormone; TTF-1, thyroid transcription factor-1. Correspondence: Dr Vijay Boggaram (email [email protected]).