Nucleic Acids Research, 2003, Vol. 31, No. 7 1845-1852
© 2003 Oxford University Press
Thyroid-specific transcription factors control Hex promoter activity
1 Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Piazzale Kolbe, 1 33100 Udine, Italy, 2 Policlinico Universitario Udine, Piazzale Kolbe, 1 33100 Udine, Italy, 3 Dipartimento di Scienze Farmacobiologiche, Complesso Nini Barbieri, 88021 Roccelletta di Borgia, Catanzaro, Italy, 4 Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro, Via Tommaso Campanella 115, 88100 Catanzaro, Italy, 5 Dipartimento di Scienze Cliniche, Università di Roma ‘la Sapienza’, Policlinico Umberto I, 00161 Roma, Italy, 6 Department of Pediatrics, Yale University School of Medicine, 4464 Congress Avenue, New Haven, CT 065208081, USA and 7 M.A.T.I. Center, Piazzale Kolbe, 1 33100 Udine, Italy
*To whom correspondence should be addressed at Dipartimento di Scienze e Tecnologie Biomediche, Piazzale Kolbe 1, 33100 Udine, Italy. Tel: +39 0432 494374; Fax: +39 0432 494379; Email: gdamante{at}makek.dstb.uniud.it
The homeobox-containing gene Hex is expressed in several cell types, including thyroid follicular cells, in which it regulates the transcription of tissue- specific genes. In this study the regulation of Hex promoter activity was investigated. Using co- transfection experiments, we demonstrated that the transcriptional activity of the Hex gene promoter in rat thyroid FRTL-5 cells is 
10-fold greater than that observed in HeLa and NIH 3T3 cell lines (which do not normally express the Hex gene). To identify the molecular mechanisms underlying these differences, we evaluated the effect of the thyroid- specific transcription factor TTF-1 on the Hex promoter activity. TTF-1 produced 3–4-fold increases in the Hex promoter activity. Gel- retardation assays and mutagenesis experiments revealed the presence of functionally relevant TTF-1 binding sites in the Hex promoter region. These in vitro data may also have functional relevance in vivo, since a positive correlation between TTF-1 and Hex mRNAs was demonstrated in human thyroid tissues by means of RT–PCR analysis. The TTF-1 effect, however, is not sufficient to explain the difference in Hex promoter activity between FRTL-5 and cells that do not express the Hex gene. For this reason, we tested whether Hex protein is able to activate the Hex promoter. Indeed, co-transfection experiments indicate that Hex protein is able to increase the activity of its own promoter in HeLa cells 4-fold. TTF-1 and Hex effects are additive: when transfected together in HeLa cells, the Hex promoter activity is increased 6–7-fold. Thus, the contemporary presence of both TTF-1 and Hex could be sufficient to explain the higher transcriptional activity of the Hex promoter in thyroid cells with respect to cell lines that do not express the Hex gene. These findings demonstrate the existence of direct cross-regulation between thyroid-specific transcription factors.
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