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Molecular and Cellular Biology, December 2006, p. 8667-8682, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00443-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mediator Modulates Gli3-Dependent Sonic Hedgehog Signaling{triangledown}

Haiying Zhou,1 Seokjoong Kim,1 Shunsuke Ishii,2 and Thomas G. Boyer1*

Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245-3207,1 Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, Tsukuba, Ibaraki 305-0074, Japan2

Received 13 March 2006/ Returned for modification 3 May 2006/ Accepted 11 September 2006

The physiological and pathological manifestations of Sonic hedgehog (Shh) signaling arise from the specification of unique transcriptional programs dependent upon key nuclear effectors of the Ci/Gli family of transcription factors. However, the underlying mechanism by which Gli proteins regulate target gene transcription in the nucleus remains poorly understood. Here, we identify and characterize a physical and functional interaction between Gli3 and the MED12 subunit within the RNA polymerase II transcriptional Mediator. We show that Gli3 binds to MED12 and intact Mediator both in vitro and in vivo through a Gli3 transactivation domain (MBD; MED12/Mediator-binding domain) whose activity derives from concerted functional interactions with both Mediator and the histone acetyltransferase CBP. Analysis of MBD truncation mutants revealed an excellent correlation between the in vivo activation strength of an MBD derivative and its ability to bind MED12 and intact Mediator in vitro, indicative of a critical functional interaction between the Gli3 MBD and the MED12 interface in Mediator. Disruption of the Gli3-MED12 interaction through dominant-negative interference inhibited, while RNA interference-mediated MED12 depletion enhanced, both MBD transactivation function and Gli3 target gene induction in response to Shh signaling. We propose that activated Gli3 physically targets the MED12 interface within Mediator in order to functionally reverse Mediator-dependent suppression of Shh target gene transcription. These findings thus link MED12 to the modulation of Gli3-dependent Shh signaling and further implicate Mediator in a broad range of developmental and pathological processes driven by Shh signal transduction.

* Corresponding author. Mailing address: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245-3207. Phone: (210) 567-7258. Fax: (210) 567-7247. E-mail: boyer{at}uthscsa.edu.

{triangledown} Published ahead of print on 25 September 2006.

Molecular and Cellular Biology, December 2006, p. 8667-8682, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00443-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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