Glucose enhances protein tyrosine phosphatase 1B gene transcription in hepatocytes.
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin receptor signal transduction pathway. We investigated the effects of glucose on PTP1B transcription in the human hepatocyte cell line Huh7. Using a reporter gene assay, we found that D-glucose dose-dependently enhanced the PTP1B promoter activity. Real-time PCR demonstrated that D-glucose also increased PTP1B mRNA expression. Protein kinase C (PKC) inhibitors partially but significantly inhibited the transactivation by D-glucose. Mithramycin, a Sp1 inhibitor, completely abrogated this transactivation. The deletion of three possible Sp1 sites in the promoter region of PTP1B significantly reduced the basal promoter activity and transactivation by D-glucose. Sp1 activation by PKC is one of the key mechanisms in the regulation of several gene expressions. Our data suggested that glucose enhanced PTP1B transcription through Sp1 activation by PKC. Increased hepatic PTP1B expression may partly explain glucose toxicity in diabetes.
Inada
Shojiro
S
Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kohasu, Nankoku, Kochi 783-8505, Japan.
Ikeda
Yukio
Y
Suehiro
Tadashi
T
Takata
Hiroshi
H
Osaki
Fumiaki
F
Arii
Kaoru
K
Kumon
Yoshitaka
Y
Hashimoto
Kozo
K
D002460:Cell Line; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008926:Plicamycin / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic
D007328:Insulin; D011500:Protein Synthesis Inhibitors; D016329:Sp1 Transcription Factor; D011493:Protein Kinase C; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D005947:Glucose; D008926:Plicamycin