O-GlcNAc integrates the proteasome and transcriptome to regulate nuclear hormone receptors

Damon B. Bowe, Andrea Sadlonova, Clifford A. Toleman, Zdenek Novak, Yong Hu, Ping Huang, Shibani Mukherjee, Timothy Whitsett, Andra R. Frost, Andrew J. Paterson, Jeffrey E. Kudlow

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8539-8550
Number of pages12
JournalMolecular and cellular biology
Volume26
Issue number22
DOIs
StatePublished - Nov 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Bowe, D. B., Sadlonova, A., Toleman, C. A., Novak, Z., Hu, Y., Huang, P., Mukherjee, S., Whitsett, T., Frost, A. R., Paterson, A. J., & Kudlow, J. E. (2006). O-GlcNAc integrates the proteasome and transcriptome to regulate nuclear hormone receptors. Molecular and cellular biology, 26(22), 8539-8550. https://doi.org/10.1128/MCB.01053-06