Nucleic Acids Research, 2001, Vol. 29, No. 2 515-526
© 2001 Oxford University Press
Antagonistic action of Six3 and Prox1 at the 
-crystallin promoter
GSF-National Research Center for Environment and Health, Institute of Mammalian Genetics, D-85764 Neuherberg, Germany, 1National Eye Institute, National Institutes of Health, Bethesda, MD, USA and 2Department of Biochemistry, Medical Science Institute, University of Dundee, Dundee, UK
-Crystallin genes are specifically expressed in the eye lens. Their promoters constitute excellent models to analyse tissue-specific gene expression. We investigated murine Cryge/f promoters of different length in lens epithelial cell lines. The most active fragment extends from position –219 to +37. Computer analysis predicts homeodomain and paired-domain binding sites for all rodent Crygd/e/f core promoters. As examples, we analysed the effects of Prox1 and Six3, which are considered important transcription factors involved in lens development. Because of endogenous Prox1 expression in N/N1003A cells, a weak stimulation of Cryge/f promoter activity was found for PROX1. In contrast, PROX1 stimulated the Crygf promoter 10-fold in CD5A cells without endogenous PROX1. In both cell lines Six3 repressed the Crygf promoter to 10% of its basal activity. Our cell transfection experiments indicated that Cryg expression increases as Six3 expression decreases. Prox1 and Six3 act antagonistically on regulation of the Crygd/e/f promoters. Functional assays using randomly mutated F-crystallin promoter fragments define a Six3-responsive element between –101 and –123 and a Prox1-responsive element between –151 and –174. Since Prox1 and Six3 are present at the beginning of lens development, expression of Crygd/e/f is predicted to remain low at this time. It increases as Six3 expression decreases during ongoing lens development.
* To whom correspondence should be addressed. Tel: +49 89 3187 2610; Fax: +49 89 3187 2210; Email: graw{at}gsf.de Present address: Eberhard Krausz, Cyclacel Ltd, Dundee, UK
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