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Molecular and Cellular Biology, November 2006, p. 8539-8550, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01053-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

O-GlcNAc Integrates the Proteasome and Transcriptome To Regulate Nuclear Hormone Receptors

Damon B. Bowe,¹ Andrea Sadlonova,² Clifford A. Toleman,³ Zdenek Novak,⁴ Yong Hu,⁵ Ping Huang,¹ Shibani Mukherjee,² Timothy Whitsett,¹ Andra R. Frost,² Andrew J. Paterson,³ and Jeffrey E. Kudlow^1,3*

Department of Pharmacology and Toxicology,¹ Department of Pathology,² Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294,³ Division of Infectious Diseases, Children's Hospital, Birmingham, Alabama 35233,⁴ Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093⁵

Received 12 June 2006/ Returned for modification 14 July 2006/ Accepted 30 August 2006

Mechanisms controlling nuclear hormone receptors are a central question to mammalian developmental and disease processes. Herein, we show that a subtle increase in O-GlcNAc levels inhibits activation of nuclear hormone receptors. In vivo, increased levels of O-GlcNAc impair estrogen receptor activation and cause a decrease in mammary ductal side-branching morphogenesis associated with loss of progesterone receptors. Increased O-GlcNAc levels suppress transcriptional expression of coactivators and of the nuclear hormone receptors themselves. Surprisingly, increased O-GlcNAc levels are also associated with increased transcription of genes encoding corepressor proteins NCoR and SMRT. The association of the enzyme O-GlcNAc transferase with these corepressors contributes to specific regulation of nuclear hormone receptors by O-GlcNAc. Overall, transcriptional inhibition is related to the integrated effect of O-GlcNAc by direct modification of critical elements of the transcriptome and indirectly through O-GlcNAc modification of the proteasome.

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* Corresponding author. Mailing address: University of Alabama, BDB 756, 1808 7th Ave. S., Birmingham, AL 35294. Phone: (205) 934-4116. Fax: (205) 934-4389. E-mail: kudlow{at}uab.edu.

Published ahead of print on 11 September 2006.

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Molecular and Cellular Biology, November 2006, p. 8539-8550, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01053-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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