scholarly journals Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

2018 ◽  
Vol 120 (1) ◽  
pp. 519-532 ◽  
Author(s):  
Shangdong Guo ◽  
Hong Lu
Keyword(s):  
Transcriptional Activity ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals Maturity-Onset Diabetes of the Young Type 1 (MODY1)-Associated Mutations R154X and E276Q in Hepatocyte Nuclear Factor 4α (HNF4α) Gene Impair Recruitment of p300, a Key Transcriptional Coactivator

2001 ◽  
Vol 15 (7) ◽  
pp. 1200-1210 ◽  
Author(s):  
Jérôme Eeckhoute ◽  
Pierre Formstecher ◽  
Bernard Laine
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Cell Function ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Β Cell ◽  
Β Cell Function ◽  
Hepatocyte Nuclear Factor 4Α

Abstract Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor involved in glucose homeostasis and is required for normal β-cell function. Mutations in the HNF4α gene are associated with maturity-onset diabetes of the young type 1. E276Q and R154X mutations were previously shown to impair intrinsic transcriptional activity (without exogenously supplied coactivators) of HNF4α. Given that transcriptional partners of HNF4α modulate its intrinsic transcriptional activity and play crucial roles in HNF4α function, we investigated the effects of these mutations on potentiation of HNF4α activity by p300, a key coactivator for HNF4α. We show here that loss of HNF4α function by both mutations is increased through impaired physical interaction and functional cooperation between HNF4α and p300. Impairment of p300-mediated potentiation of HNF4α transcriptional activity is of particular importance for the E276Q mutant since its intrinsic transcriptional activity is moderately affected. Together with previous results obtained with chicken ovalbumin upstream promoter-transcription factor II, our results highlight that impairment of recruitment of transcriptional partners represents an important mechanism leading to abnormal HNF4α function resulting from the MODY1 E276Q mutation. The impaired potentiations of HNF4α activity were observed on the promoter of HNF1α, a transcription factor involved in a transcriptional network and required for β-cell function. Given its involvement in a regulatory signaling cascade, loss of HNF4α function may cause reduced β-cell function secondary to defective HNF1α expression. Our results also shed light on a better structure-function relationship of HNF4α and on p300 sequences involved in the interaction with HNF4α.

scholarly journals Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

2006 ◽  
Vol 397 (1) ◽  
pp. 159-168 ◽  
Author(s):  
Soo-Hee Park ◽  
Christopher A. Wiwi ◽  
David J. Waxman
Keyword(s):  
Growth Hormone ◽  
Tyrosine Phosphorylation ◽  
Cross Talk ◽  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Dominant Negative ◽  
Janus Kinase ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4α (hepatocyte nuclear factor 4α), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4α strongly inhibited β-casein and ntcp (Na+/taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-γ-stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4α towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4α on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4α, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4α inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4α blocked GH-stimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4α exhibit bi-directional cross-talk that may augment HNF4α-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4α on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

scholarly journals The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4α activities and introduces a PKA phosphorylation site in its DNA-binding domain

2004 ◽  
Vol 383 (3) ◽  
pp. 573-580 ◽  
Author(s):  
Bénédicte OXOMBRE ◽  
Mostafa KOUACH ◽  
Ericka MOERMAN ◽  
Pierre FORMSTECHER ◽  
Bernard LAINE
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Transcriptional Activity ◽  
Phosphorylation Site ◽  
Binding Domain ◽  
Nuclear Factor ◽  
Dna Binding Domain ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

HNF4α (hepatocyte nuclear factor 4α) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic β-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4α gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115→Ser) HNF4α mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4α-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic β-cell lines, this mutation resulted in strong impairments of HNF4α transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1α, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115→Glu) mutation mimicking phosphorylation reduced HNF4α DNA-binding and transcriptional activities. Our results may account for the 100% penetrance of diabetes in human carriers of this mutation. In addition, they suggest that introduction of a phosphorylation site in the DNA-binding domain may represent a new mechanism by which a MODY1 mutation leads to loss of HNF4α function.

scholarly journals H19 Is Expressed in Hybrid Hepatocyte Nuclear Factor 4α + Periportal Hepatocytes but Not Cytokeratin 19 + Cholangiocytes in Cholestatic Livers

2018 ◽  
Vol 2 (11) ◽  
pp. 1356-1368 ◽  
Author(s):  
YanChao Jiang ◽  
Yi Huang ◽  
ShiYing Cai ◽  
YongFeng Song ◽  
James L. Boyer ◽  
...  
Keyword(s):  
Cytokeratin 19 ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α
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