O-GlcNAc integrates the proteasome and transcriptome to regulate nuclear hormone receptors.
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.
Bowe
Damon B
DB
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Sadlonova
Andrea
A
Toleman
Clifford A
CA
Novak
Zdenek
Z
Hu
Yong
Y
Huang
Ping
P
Mukherjee
Shibani
S
Whitsett
Timothy
T
Frost
Andra R
AR
Paterson
Andrew J
AJ
Kudlow
Jeffrey E
JE
D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D042361:Mammary Glands, Human / Q000196:embryology / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D046988:Proteasome Endopeptidase Complex