Transcriptional Regulation of Human UGT1A1 Gene Expression: Activated Glucocorticoid Receptor Enhances constitutive Androstane Receptor/Pregnane X Receptor-Mediated UDP-Glucuronosyltransferase 1A1 Regulation with Glucocorticoid Receptor-Interacting Protein 1

2004 ◽  
Vol 67 (3) ◽  
pp. 845-855 ◽  
Author(s):  
Junko Sugatani ◽  
Shinichi Nishitani ◽  
Kasumi Yamakawa ◽  
Kouichi Yoshinari ◽  
Tatsuya Sueyoshi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Glucocorticoid Receptor ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Interacting Protein ◽  
Ugt1a1 Gene ◽  
Udp Glucuronosyltransferase

scholarly journals Comparison of the Hepatic Effects of Phenobarbital in Chimeric Mice Containing Either Rat or Human Hepatocytes With Humanized Constitutive Androstane Receptor and Pregnane X Receptor Mice

2020 ◽  
Vol 177 (2) ◽  
pp. 362-376
Author(s):  
Tomoya Yamada ◽  
Ayako Ohara ◽  
Naoya Ozawa ◽  
Keiko Maeda ◽  
Miwa Kondo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Tumor ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Rat Hepatocytes ◽  
Global Gene Expression ◽  
Human Hepatocytes ◽  
Chimeric Mouse ◽  
Chimeric Mice ◽  
Wild Type

Abstract Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, because rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild-type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/β-catenin signaling when compared with those of hCAR/hPXR mice, wild-type mice, and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators whereas the hCAR/hPXR mouse is not.

Regulation of Pregnane X Receptor (PXR) Function and UGT1A1 Gene Expression by Posttranslational Modification of PXR Protein

2012 ◽  
Vol 40 (10) ◽  
pp. 2031-2040 ◽  
Author(s):  
Junko Sugatani ◽  
Takahiro Uchida ◽  
Masatoshi Kurosawa ◽  
Masahiko Yamaguchi ◽  
Yasuhiro Yamazaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Posttranslational Modification ◽  
Pregnane X Receptor ◽  
Ugt1a1 Gene

Insulin inhibits glucocorticoid-stimulated L-type 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene expression by activation of the c-Jun N-terminal kinase pathway

2001 ◽  
Vol 353 (2) ◽  
pp. 267-273 ◽  
Author(s):  
Elisabet DE LOS PINOS ◽  
Silvia FERNÁNDEZ DE MATTOS ◽  
Manel JOAQUIN ◽  
Albert TAULER
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Glucocorticoid Receptor ◽  
Map Kinase ◽  
Inhibitory Effect ◽  
Interacting Protein ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Ribosomal S6 Kinase ◽  
Phosphoinositide 3 Kinase

The hepatic isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PF2K/Fru-2,6-BPase) is transcriptionally stimulated by glucocorticoids, whereas insulin blocks this stimulatory effect. Although this inhibitory effect has been extensively reported, nothing is known about the signalling pathway responsible. We have used well-characterized inhibitors for proteins involved in different signalling cascades to assess the involvement of these pathways on the transcriptional regulation of glucocorticoid-stimulated PF2K/Fru-2,6-BPase by insulin. Our results demonstrate that the phosphoinositide 3-kinase, p70/p85 ribosomal S6 kinase, extracellular signal-regulated protein kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinase pathways are not involved in the inhibitory effect of insulin on glucocorticoid-stimulated PF2K/Fru-2,6-BPase. To evaluate the implication of the MAP kinase/ERK kinase (MEK)-4Őstress-activated protein kinaseŐc-Jun-N-terminal protein kinase (‘JNKŐSAPK’) pathway we overexpressed the N-terminal JNK-binding domain of the JNK-interacting protein 1 (‘JIP-1’), demonstrating that activation of JNK is necessary for the insulin inhibitory effect. Moreover, overexpression of MEK kinase 1 and JNKŐhaemagglutinin resulted in the inhibition of the glucocorticoid-stimulated PF2K/Fru-2,6-BPase. These results provide clear and specific evidence for the role of JNK in the insulin inhibition of glucocorticoid-stimulated PF2K/Fru-2,6-BPase gene expression. In addition, we performed experiments with a mutant of the glucocorticoid receptor in which the JNK phosphorylation target Ser-246 had been mutated to Ala. Our results demonstrate that the phosphorylation of the glucocorticoid receptor on Ser-246 is not responsible for the JNK repression of glucocorticoid-stimulated PF2K/Fru-2,6-BPase gene expression.

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