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 Activation of Nuclear Factor κb and bcl-x Survival Gene Expression by Nerve Growth Factor Requires Tyrosine Phosphorylation of IκBα

2001 ◽  
Vol 152 (4) ◽  
pp. 753-764 ◽  
Author(s):  
Nguyen Truc Bui ◽  
Antonia Livolsi ◽  
Jean-Francois Peyron ◽  
Jochen H.M. Prehn
Keyword(s):  
Gene Expression ◽  
Tyrosine Phosphorylation ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Nuclear Factor ◽  
Human Neuroblastoma ◽  
Tnf Α

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-κB (NFκB). We investigated the effect of NGF on the expression of Bcl-xL, an anti–apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1–10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFκB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFκB p65 subunit. NGF-induced NFκB activity and Bcl-xL expression were inhibited in cells overexpressing the NFκB inhibitor, IκBα. Unlike tumor necrosis factor-α (TNF-α), however, NGF-induced NFκB activation occurred without significant degradation of IκBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein–tagged IκBα. Moreover, in contrast to TNF-α, NGF failed to phosphorylate IκBα at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IκBα potently suppressed NFG-, but not TNF-α–induced NFκB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-α–, but not NGF-induced NFκB activation. We conclude that NGF and TNF-α induce different signaling pathways in neurons to activate NFκB and bcl-x gene expression.

scholarly journals Thioesterase Activity and Acyl-CoA/Fatty Acid Cross-talk of Hepatocyte Nuclear Factor-4α

2005 ◽  
Vol 280 (26) ◽  
pp. 24451-24461 ◽  
Author(s):  
Rachel Hertz ◽  
Bella Kalderon ◽  
Tamara Byk ◽  
Ina Berman ◽  
Ghadeer Za'tara ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cross Talk ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4Α

scholarly journals Promoter-Specific Repression of Hepatocyte Nuclear Factor (HNF)-1β and HNF-1α Transcriptional Activity by an HNF-1β Missense Mutant Associated with Type 5 Maturity-Onset Diabetes of the Young with Hepatic and Biliary Manifestations

2004 ◽  
Vol 89 (3) ◽  
pp. 1369-1378 ◽  
Author(s):  
Sachiko Kitanaka ◽  
Yuko Miki ◽  
Yasuhide Hayashi ◽  
Takashi Igarashi
Keyword(s):  
Functional Analysis ◽  
Dna Binding ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
Repressive Effect

Abstract Mutations in the hepatocyte nuclear factor (HNF)-1β lead to type 5 maturity-onset diabetes of the young (MODY5). HNF-1β forms a homodimer or a heterodimer with HNF-1α and regulates various target genes. HNF-1β mutations are rare, and no functional analysis has been performed in conjunction with HNF-1α. HNF-1β is expressed in the liver and biliary system and controls liver-specific and bile acid-related genes. Moreover, liver-specific Hnf-1β knockout mice present with severe jaundice. However, no patients with HNF-1β mutations have biliary manifestations. In this report, we found a novel missense mutation in the HNF-1β gene in a patient with neonatal cholestasis and liver dysfunction together with the common features of MODY5. Functional analysis revealed that the mutant HNF-1β had diminished transcriptional activity by loss of the DNA binding activity. The mutant had a promoter-specific dominant-negative transcriptional effect on wild-type HNF-1β and inhibited its DNA binding. Moreover, the mutant had a promoter- and cell-specific transcriptional repressive effect on HNF-1α and a promoter-specific inhibitory effect on HNF-1α DNA binding. From these results, we considered that the different phenotype of patients with HNF-1β mutations might be caused by the different HNF-1β activity in conjunction with the different repression of HNF-1α activity in selected promoters and tissues.

scholarly journals Zyxin regulates migration of renal epithelial cells through activation of hepatocyte nuclear factor-1β

2013 ◽  
Vol 305 (1) ◽  
pp. F100-F110 ◽  
Author(s):  
Yun-Hee Choi ◽  
Brian T. McNally ◽  
Peter Igarashi
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Nuclear Translocation ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Epithelial Tissue ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Lim Domain ◽  
Renal Epithelial Cells

Hepatocyte nuclear factor-1β (HNF-1β) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1β in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1β in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1β. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1β. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1β. Overexpression of zyxin stimulates the transcriptional activity of HNF-1β, whereas small interfering RNA silencing of zyxin inhibits HNF-1β-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1β-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant-negative mutant HNF-1β, knockdown of zyxin, or inhibition of Akt inhibits EGF-stimulated cell migration. These findings reveal a novel pathway by which extracellular signals are transmitted to the nucleus to regulate the activity of a transcription factor that is essential for renal epithelial differentiation.

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 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 Activation of nuclear factor-κB is necessary for myotrophin-induced cardiac hypertrophy

2002 ◽  
Vol 159 (6) ◽  
pp. 1019-1028 ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Nicole H. Purcell ◽  
Anning Lin ◽  
Subha Sen
Keyword(s):  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Spontaneously Hypertensive Rat ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Hypertrophic Response ◽  
Calphostin C ◽  
Iκb Kinase

The transcription factor nuclear factor-κB (NF-κB) regulates expression of a variety of genes involved in immune responses, inflammation, proliferation, and programmed cell death (apoptosis). Here, we show that in rat neonatal ventricular cardiomyocytes, activation of NF-κB is involved in the hypertrophic response induced by myotrophin, a hypertrophic activator identified from spontaneously hypertensive rat heart and cardiomyopathic human hearts. Myotrophin treatment stimulated NF-κB nuclear translocation and transcriptional activity, accompanied by IκB-α phosphorylation and degradation. Consistently, myotrophin-induced NF-κB activation was enhanced by wild-type IκB kinase (IKK) β and abolished by the dominant-negative IKKβ or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc) and also enhanced protein synthesis were partially inhibited by a potent NF-κB inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C. Expression of the dominant-negative form of IκB-α or IKKβ also partially inhibited the transcriptional activity of ANF induced by myotrophin. These findings suggest that the PKC–IKK–NF-κB pathway may play a critical role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.

Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative

Diabetes ◽  
1998 ◽  
Vol 47 (8) ◽  
pp. 1231-1235 ◽  
Author(s):  
K. Yamagata ◽  
Q. Yang ◽  
K. Yamamoto ◽  
H. Iwahashi ◽  
J. Miyagawa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor
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