An essential role of cAMP response element-binding protein in epidermal growth factor-mediated induction of sodium/glucose cotransporter 1 gene expression and intestinal glucose uptake.
The sodium/glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. Its expression is decreased in individuals with intestinal inflammatory disorders and is correlated with the pathogenesis of disease. The aim of this study was to understand the regulatory mechanism of the SGLT1 gene. Using the trinitrobenzene sulfonic acid-induced mouse models of intestinal inflammation, we observed decreased SGLT1 expression in the inflamed intestine was positively correlated with the mucosal level of epidermal growth factor (EGF) and activated CREB. Overexpression of EGF demonstrated that the effect of EGF on intestinal glucose uptake was primarily due to the increased level of SGLT1. We identified an essential cAMP binding element (CRE) confers EGF inducibility in the human SGLT1 gene promoter. ChIP assay further demonstrated the increased binding of CREB and CBP to the SGLT1 gene promoter in EGF-treated cells. In addition, the EGFR- and PI3K-dependent CREB phosphorylations are involved in the EGF-mediated SGLT1 expression. This is the first report to demonstrate that CREB is involved in EGF-mediated transcription regulation of SGLT1 gene in the normal and inflamed intestine, which can provide potential therapeutic applications for intestinal inflammatory disorders.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Chun-Wen
CW
Wang
School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, ROC.
Wen-Liang
WL
Chang
Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
Yu-Chuan
YC
Huang
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC.
Fang-Chi
FC
Chou
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC.
Fang-Na
FN
Chan
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC.
Shih-Chieh
SC
Su
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC.
Shu-Fen
SF
Huang
School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
Hui-Hsuan
HH
Ko
School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
Yi-Ling
YL
Ko
School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, ROC.
Hang-Chin
HC
Lin
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC. Electronic address: tcchang@ndmctsgh.edu.tw.
Tsu-Chung
TC
Chang
D000818:Animals; D018938:Caco-2 Cells; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000502:physiology; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D004815:Epidermal Growth Factor; D005947:Glucose
Caco-2 cells; Gene expression; Glucose transporter; Sodium/glucose cotransporter 1 promoter; Transcriptional factors