TY - JOUR
T1 - The role of O-linked GlcNAc modification on the glucose response of ChREBP
AU - Sakiyama, Haruhiko
AU - Fujiwara, Noriko
AU - Noguchi, Takahiro
AU - Eguchi, Hironobu
AU - Yoshihara, Daisaku
AU - Uyeda, Kosaku
AU - Suzuki, Keiichiro
N1 - Funding Information:
We thank Dr. Masashi Fukasawa (Department of Biochemistry, Nagasaki International University) for providing many valuable suggestions. This work was supported by a Grant-in-Aid for Scientific Research (21700710); a Grant-in-Aid for Researchers, Hyogo College of Medicine , 2008; a Hitech Research Center grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan , and a Grant from Hyogo Science and Technology Association (H.S.).
PY - 2010/11/26
Y1 - 2010/11/26
N2 - The carbohydrate response element-binding protein (ChREBP) functions as a transcription factor in mediating the glucose-activated gene expression of multiple liver enzymes, which are responsible for converting excess carbohydrate to storage fat. ChREBP is translocated into the nucleus in response to high glucose levels, and then up-regulates transcriptional activity. Although this glucose activation of ChREBP is generally observed only in liver cells, overexpression of wild type max-like protein X (Mlx), but not an inactive mutant Mlx, resulted in the exhibition of the ChREBP functions also in a human kidney cell line. Because high glucose conditions induce the glycosylation of cellular proteins, the effect of O-linked GlcNAc modification on ChREBP functions was examined. Treatment with an O-GlcNAcase inhibitor (PUGNAc), which increases the O-linked GlcNAc modification of cellular proteins, caused an increase in the glucose response of ChREBP. In contrast, treatment with a glutamine fructose amidotransferase inhibitor (DON), which decreases O-GlcNAcylation by inhibiting the hexosamine biosynthetic pathway, completely blocked the glucose response of ChREBP. These results suggest that the O-linked glycosylation of ChREBP itself or other proteins that regulate ChREBP is essential for the production of functional ChREBP.
AB - The carbohydrate response element-binding protein (ChREBP) functions as a transcription factor in mediating the glucose-activated gene expression of multiple liver enzymes, which are responsible for converting excess carbohydrate to storage fat. ChREBP is translocated into the nucleus in response to high glucose levels, and then up-regulates transcriptional activity. Although this glucose activation of ChREBP is generally observed only in liver cells, overexpression of wild type max-like protein X (Mlx), but not an inactive mutant Mlx, resulted in the exhibition of the ChREBP functions also in a human kidney cell line. Because high glucose conditions induce the glycosylation of cellular proteins, the effect of O-linked GlcNAc modification on ChREBP functions was examined. Treatment with an O-GlcNAcase inhibitor (PUGNAc), which increases the O-linked GlcNAc modification of cellular proteins, caused an increase in the glucose response of ChREBP. In contrast, treatment with a glutamine fructose amidotransferase inhibitor (DON), which decreases O-GlcNAcylation by inhibiting the hexosamine biosynthetic pathway, completely blocked the glucose response of ChREBP. These results suggest that the O-linked glycosylation of ChREBP itself or other proteins that regulate ChREBP is essential for the production of functional ChREBP.
KW - ChREBP
KW - Mlx
KW - O-GlcNAc
KW - Subcellular localization
KW - Transcription factor
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U2 - 10.1016/j.bbrc.2010.10.113
DO - 10.1016/j.bbrc.2010.10.113
M3 - Article
C2 - 21036147
AN - SCOPUS:78649443736
SN - 0006-291X
VL - 402
SP - 784
EP - 789
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -