scholarly journals Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

2007 ◽  
Vol 192 (1) ◽  
pp. 141-147 ◽  
Author(s):  
Sachiko Kitanaka ◽  
Utako Sato ◽  
Takashi Igarashi
Keyword(s):  
Human Insulin ◽  
Gene Promoter ◽  
Nuclear Factor ◽  
Multidrug Resistance Protein ◽  
Hepatocyte Nuclear Factor ◽  
Wild Type ◽  
Multidrug Resistance Protein 2 ◽  
Human Insulin Gene ◽  
Igf I ◽  
Resistance Protein

Mutations in hepatocyte nuclear factor-1β (HNF-1β) lead to type 5 maturity-onset diabetes of the young (MODY5). Moreover, mutations in the HNF-1β gene might cause multiorgan abnormalities including renal diseases, genital malformations, and abnormal liver function. The objective of this study was to investigate the molecular mechanism of diabetes mellitus, intrauterine growth retardation, and cholestasis observed in MODY5 patients. We analyzed the transactivity of wild-type and three mutant HNF-1β on native human insulin, IGF-I, and multidrug resistance protein 2 (MRP2) promoters in combination with HNF-1α, using a reporter-assay system in transiently transfected mammalian cells. In the human insulin gene promoter, we found that the cooperation of HNF-1α and HNF-1β is prominent. Absence of this cooperation was observed in all of the HNF-1β mutants. In the human IGF-I and MRP2 promoters, we found that the HNF-1β His153Asn (H153N) mutant had a mutant-specific repressive effect on both HNF-1α and wild-type HNF-1β transactivity. Absence of the cooperation of HNF-1β mutants with HNF-1α in the human insulin gene promoter might be one cause of defective insulin secretion. The H153N mutant-specific repression of HNF-1α and HNF-1β transactivity in human IGF-I and MRP2 promoters might explain the case-specific clinical features of growth retardation and cholestasis observed only in early infancy. We found differential property of HNF-1α/HNF-1β activity and the effect of HNF-1β mutants by the promoters. We consider that analyses of HNF-1β mutants on the intended human native promoters in combination with HNF-1α may be useful in investigating the molecular mechanisms of the various features in MODY5.

Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide

2020 ◽  
Vol 21 (13) ◽  
pp. 1060-1067
Author(s):  
Xiaocui Li ◽  
Yushan Xie ◽  
Wei Qu ◽  
Xiaojun Ou ◽  
Xiaowen Ou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Breast Cancer Resistance Protein ◽  
Gene Knockout ◽  
Multidrug Resistance Protein ◽  
Cancer Resistance ◽  
Wild Type ◽  
Multidrug Resistance Protein 2 ◽  
Intestinal Microsomes ◽  
Resistance Protein

Background: Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-β-glucuronide (L-10-G) vivo. Objective: To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the disposition of L-10-G. Methods: The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined. Results: After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and 16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with wild-type FVB mice (P < 0.05). After gavage with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively, than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared to the wild-type FVB mice (P < 0.05). Conclusion: Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.

HEPATOCYTE NUCLEAR FACTOR-1α INHIBITS INSULIN PROMOTER FACTOR 1-DEPENDENT TRANSACTIVATION OF THE HUMAN INSULIN GENE

2001 ◽  
Vol 27 (1-2) ◽  
pp. 63-74 ◽  
Author(s):  
Kenichi Yamakawa ◽  
Hironori Yamasaki ◽  
Masako Ozaki ◽  
Mikako-Degawa Yamauchi ◽  
Naruhiro Fujita ◽  
...  
Keyword(s):  
Human Insulin ◽  
Insulin Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Human Insulin Gene ◽  
Insulin Promoter ◽  
Hepatocyte Nuclear Factor 1Α

scholarly journals Elevated Glucose Attenuates Human Insulin Gene Promoter Activity in INS-1 Pancreatic β-Cells via Reduced Nuclear Factor Binding to the A5/Core and Z Element

2005 ◽  
Vol 19 (5) ◽  
pp. 1343-1360 ◽  
Author(s):  
Maria F. Pino ◽  
Diana Z. Ye ◽  
Katrina D. Linning ◽  
Christopher D. Green ◽  
Barton Wicksteed ◽  
...  
Keyword(s):  
Human Insulin ◽  
Promoter Activity ◽  
Gene Promoter ◽  
Insulin Gene ◽  
Nuclear Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Factor Binding ◽  
Human Insulin Gene ◽  
Elevated Glucose

Human Insulin Gene Is a Target Gene of Hepatocyte Nuclear Factor-1α (HNF-1α) and HNF-1β

1999 ◽  
Vol 263 (2) ◽  
pp. 566-569 ◽  
Author(s):  
Kohei Okita ◽  
Qin Yang ◽  
Kazuya Yamagata ◽  
Kerstin A. Hangenfeldt ◽  
Jun-ichiro Miyagawa ◽  
...  
Keyword(s):  
Human Insulin ◽  
Target Gene ◽  
Insulin Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Human Insulin Gene ◽  
Hepatocyte Nuclear Factor 1Α

scholarly journals Upstream region of rat serum albumin gene promoter contributes to promoter activity: presence of functional binding site for hepatocyte nuclear factor-3

1999 ◽  
Vol 338 (2) ◽  
pp. 241-249 ◽  
Author(s):  
Chin-Hui HSIANG ◽  
Norman W. MARTEN ◽  
Daniel S. STRAUS
Keyword(s):  
Serum Albumin ◽  
Hepg2 Cells ◽  
Promoter Activity ◽  
Gene Promoter ◽  
Upstream Region ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Rat Serum ◽  
Albumin Gene ◽  
Rat Serum Albumin

Transcription of the serum albumin gene occurs almost exclusively in the liver and is controlled in part by a strong liver-specific promoter. The upstream region of the serum albumin gene promoter is highly conserved among species and is footprinted in vitro by a number of nuclear proteins. However, the role of the upstream promoter region in regulating transcription and the identity of the transcription factors that bind to this region have not been established. In the present study, deletion analysis of the rat serum albumin promoter in transiently transfected HepG2 cells demonstrated that elimination of the region between -207 and -153 bp caused a two-fold decrease in promoter activity (P< 0.05). Additional analysis of the -207 to -124 bp promoter interval led to the identification of two potential binding sites for hepatocyte nuclear factor-3 (HNF-3) located at -168 to -157 bp (site X) and -145 to -134 bp (site Y). Electrophoretic mobility-shift assays performed with the HNF-3 X and Y sites demonstrated that both sites are capable of binding HNF-3α and HNF-3β. Placement of a single copy of the HNF-3 X site upstream from a minimal promoter increased promoter activity by about four-fold in HepG2 cells, and the reporter construct containing this site could be transactivated if co-transfected with an HNF-3 expression construct. Furthermore, inactivation of the HNF-3 X site by site-directed mutagenesis within the context of the -261 bp albumin promoter construct resulted in a 40% decrease in transcription (P< 0.05). These results indicate that the positive effect of the -207 to -153 bp promoter interval is attributable to the presence of the HNF-3 X site within this interval. Additional results obtained with transfected HepG2 cells suggest that the HNF-3 Y site plays a lesser role in activation of transcription than the X site.

scholarly journals Multidrug Resistance Protein 2 Implicates Anticancer Drug-Resistance to Sorafenib

2011 ◽  
Vol 34 (3) ◽  
pp. 433-435 ◽  
Author(s):  
Yoshihiko Shibayama ◽  
Kou Nakano ◽  
Hiroshi Maeda ◽  
Miyuki Taguchi ◽  
Ryuji Ikeda ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Anticancer Drug ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 2 ◽  
Resistance Protein ◽  
Anticancer Drug Resistance
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