The mouse Muc5b mucin gene is transcriptionally regulated by thyroid transcription factor-1 (TTF-1) and GATA-6 transcription factors.
MUC5B is one of the major mucin genes expressed in the respiratory tract. Previous studies in our laboratory have demonstrated that MUC5B is expressed in human lung adenocarcinomas and during lung morphogenesis. Moreover, in human lung adenocarcinoma tissues, a converse correlation between MUC5B and thyroid transcription factor-1 (TTF-1) expression, a lung-specific transcription factor, has been established. However, the molecular mechanisms that govern the regulation of MUC5B expression in the lung are largely unknown. In order to better understand the biological role of MUC5B in lung pathophysiology, we report the characterization of the promoter region of the mouse Muc5b mucin gene. The promoter is flanked by a TATA box (TACATAA) identical to that in the human gene. Human and murine promoters share 67.5% similarity over the first 170 nucleotides. By RT-PCR, co-transfection studies and gel-shift assays, we show that Muc5b promoter activity is completely inhibited by TTF-1, whereas factors of the GATA family (GATA-4/GATA-5/GATA-6) are activators. Together, these results demonstrate, for the first time, that Muc5b is a target gene of transcription factors (TTF-1, GATA-6) involved in lung differentiation programs during development and carcinogenesis, and identify TTF-1 as a strong repressor of Muc5b. The characterization of the structural and functional features of the Muc5b mucin gene will provide us with a strong base to develop studies in murine models aimed at the identification of its biological role in lung pathophysiology.
Inserm, U837, Jean Pierre Aubert Research Center, Lille, France. nicolas.jonckheere@inserm.fr
Nicolas
N
Jonckheere
Amélie
A
Velghe
Marie-Paule
MP
Ducourouble
Marie-Christine
MC
Copin
Ingrid B
IB
Renes
Isabelle
I
Van Seuningen
D000230:Adenocarcinoma / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000378:metabolism; D000231:Adenocarcinoma, Papillary / Q000378:metabolism; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050992:GATA5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D055257:Mucin-5B / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D017384:Sequence Deletion / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D050991:GATA4 Transcription Factor; D050992:GATA5 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494756:Gata5 protein, mouse; C524578:MUC5B protein, human; C524579:Muc5b protein, mouse; D055257:Mucin-5B; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D004247:DNA