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Molecular and Cellular Biology, October 2008, p. 6094-6103, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00539-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Deficiency of Mbd2 Attenuates Wnt Signaling{triangledown} ,{dagger}

Toby J. Phesse,1,{ddagger} Lee Parry,1 Karen R. Reed,1 Kenneth B. Ewan,1 Trevor C. Dale,1 Owen J. Sansom,2 and Alan R. Clarke1*

Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom,1 The Beatson Institute, Garscube Estate, Glasgow G61 1BD, United Kingdom2

Received 2 April 2008/ Returned for modification 2 June 2008/ Accepted 8 July 2008

We have previously shown that deficiency of the methyl binding domain protein Mbd2 dramatically reduces adenoma burden on an ApcMin/+ background. To investigate the mechanism underlying this phenomenon, we have determined the effect of Mbd2 deficiency upon the phenotypes imposed by the conditional deletion of Apc in the small intestine. Microarray analysis demonstrated a partial suppression of the Wnt pathway in the absence of Mbd2. Mbd2 deficiency also influenced one immediate cellular consequence of Apc loss, with normalization of Paneth cell positioning. From a mechanistic perspective, we show that deficiency of Mbd2 elevates levels of the known Wnt target Lect2, and we confirm here that Mbd2 binds the Lect2 promoter in association with NuRD. Furthermore, we show that Lect2 is capable of functioning as a Wnt pathway repressor. These results therefore provide a mechanistic basis for the epigenetic control of adenoma formation mediated through Mbd2.

* Corresponding author. Mailing address: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3US, United Kingdom. Phone: 011-44-02920 874609. Fax: 011-44-02920 874116. E-mail: clarkear{at}cf.ac.uk

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.

Molecular and Cellular Biology, October 2008, p. 6094-6103, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00539-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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