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Nucleic Acids Research Advance Access published online on January 23, 2007
Nucleic Acids Research, doi:10.1093/nar/gkl1105
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© 2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

The MH1 domain of Smad3 interacts with Pax6 and represses autoregulation of the Pax6 P1 promoter

Timothy Grocott1, Victoria Frost1, Marjorie Maillard1, Terje Johansen2, Grant N. Wheeler1, Lucy J. Dawes1, I. Michael Wormstone1 and Andrew Chantry1,*

1School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK and 2Department of Biochemistry, Institute of Medical Biology, University of Tromso, 9037 Tromso, Norway

*To whom correspondence should be addressed. Tel: 44 1603 593551; Fax: 44 1603 592250; Email: a.chantry{at}uea.ac.uk

Pax6 transcription is under the control of two main promoters (P0 and P1), and these are autoregulated by Pax6. Additionally, Pax6 expression is under the control of the TGFß superfamily, although the precise mechanisms of such regulation are not understood. The effect of TGFß on Pax6 expression was studied in the FHL124 lens epithelial cell line and was found to cause up to a 50% reduction in Pax6 mRNA levels within 24 h. Analysis of luciferase reporters showed that Pax6 autoregulation of the P1 promoter, and its induction of a synthetic promoter encoding six paired domain-binding sites, were significantly repressed by both an activated TGFß receptor and TGFß ligand stimulation. Subsequently, a novel Pax6 binding site in P1 was shown to be necessary for autoregulation, indicating a direct influence of Pax6 protein on P1. In transfected cells, and endogenously in FHL124 cells, Pax6 co-immunoprecipitated with Smad3 following TGFß receptor activation, while in GST pull-down experiments, the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6 paired domain. Finally, in DNA adsorption assays, activated Smad3 inhibited Pax6 from binding the consensus paired domain recognition sequence. We hypothesize that the Pax6 autoregulatory loop is targeted for repression by the TGFß/Smad pathway, and conclude that this involves diminished paired domain DNA-binding function resulting from a ligand-dependant interaction between Pax6 and Smad3.


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