scholarly journals Thyroid Hormone Receptor Interacting Protein 3 (Trip3) Is a Novel Coactivator of Hepatocyte Nuclear Factor-4 

Diabetes ◽  
2002 ◽  
Vol 51 (4) ◽  
pp. 910-914 ◽  
Author(s):  
H. Iwahashi ◽  
K. Yamagata ◽  
I. Yoshiuchi ◽  
J. Terasaki ◽  
Q. Yang ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Interacting Protein ◽  
Hepatocyte Nuclear Factor 4

scholarly journals Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors.

1995 ◽  
Vol 15 (9) ◽  
pp. 5131-5143 ◽  
Author(s):  
G Jiang ◽  
L Nepomuceno ◽  
K Hopkins ◽  
F M Sladek
Keyword(s):  
Nuclear Receptors ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Specific Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Mobility Shift ◽  
Receptor Alpha ◽  
Hepatocyte Nuclear Factor 4

Hepatocyte nuclear factor 4 (HNF-4), a highly conserved member of the steroid hormone receptor superfamily critical for development and liver-specific gene expression, is very similar to another superfamily member, retinoid X receptor alpha (RXR alpha), in overall amino acid sequence and DNA binding specificity. Since RXR alpha is known to heterodimerize with many other nuclear receptors, the formation of heterodimers between HNF-4 and RXR alpha was examined. With the electrophoretic mobility shift assay, coimmunoprecipitation, and transient transfection assays, it is shown that, unlike other nuclear receptors, HNF-4 does not form heterodimers with RXR alpha either in the presence or in the absence of DNA. We also show that in vitro-translated HNF-4 does not form heterodimeric complexes on DNA with a number of other receptors, including RXR beta, RXR gamma, retinoic acid receptor alpha, or thyroid hormone receptor alpha. To investigate the hypothesis that the lack of heterodimerization between HNF-4 and RXR alpha is due to a strong homodimerization activity of HNF-4, glycerol gradient sedimentation and kinetic analysis were used to show that HNF-4 is in fact a stable homodimer in solution. Finally, immunohistochemistry is used to show that the HNF-4 protein is found exclusively in the nuclei in both HepG2 cells, which express endogenous HNF-4, and transfected COS cells, which overexpress HNF-4. These findings lead us to propose that HNF-4 defines a new subclass of nuclear receptors which reside primarily in the nucleus and which bind DNA and regulate transcription as homodimers.

scholarly journals The CYP2B2 phenobarbital response unit contains binding sites for hepatocyte nuclear factor 4, PBX–PREP1, the thyroid hormone receptor β and the liver X receptor

2005 ◽  
Vol 388 (2) ◽  
pp. 407-418 ◽  
Author(s):  
Marie-Josée BEAUDET ◽  
Marc DESROCHERS ◽  
Antoine Amaury LACHAUD ◽  
Alan ANDERSON
Keyword(s):  
Transcription Factor ◽  
Thyroid Hormone ◽  
Binding Sites ◽  
Thyroid Hormone Receptor ◽  
Transcription Factor Binding ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Factor Binding ◽  
Hepatocyte Nuclear Factor 4 ◽  
Thyroid Hormone Receptor Β

A 163 bp enhancer in the CYP2B2 5′ flank confers PB (phenobarbital) inducibility and constitutes a PBRU (PB response unit). The PBRU contains several transcription factor binding sites, including NR1, NR2 and NR3, which are direct repeats separated by 4 bp of the nuclear receptor consensus half-site AGGTCA, as well as an ER (everted repeat) separated by 7 bp (ER-7). Constitutive androstane receptor (CAR)–RXR (retinoic X receptor) heterodimers are known to bind to NR1, NR2 and NR3. Electrophoretic mobility-shift analysis using nuclear extracts from livers of untreated or PB-treated rats revealed binding of several other proteins to different PBRU elements. Using supershift analysis and in vitro coupled transcription and translation, the proteins present in four retarded complexes were identified as TRβ (thyroid hormone receptor β), LXR (liver X receptor), HNF-4 (hepatocyte nuclear factor 4) and heterodimers of PBX–PREP1 (pre-B cell homoeobox–Pbx regulatory protein 1). LXR–RXR heterodimers bound to NR3 and TRβ bound to NR3, NR1 and ER-7, whereas the PBX–PREP1 site is contained within NR2. The HNF-4 site overlaps with NR1. A mutation described previously, GRE1m1, which decreases PB responsiveness, increased the affinity of this site for HNF-4. The PBRU also contains a site for nuclear factor 1. The PBRU thus contains a plethora of transcription factor binding sites. The profiles of transcription factor binding to NR1 and NR3 were quite similar, although strikingly different from, and more complex than, that of NR2. This parallels the functional differences in conferring PB responsiveness between NR1 and NR3 on the one hand, and NR2 on the other.

Evidence for evolutionary conservation of a physical linkage between the human BAF60b, a subunit of SWI/SNF complex, and thyroid hormone receptor interacting protein-1 genes on chromosome 17

Genome ◽  
1999 ◽  
Vol 42 (3) ◽  
pp. 545-549
Author(s):  
Rama Mohan Surabhi ◽  
Lisa Dawn Daly ◽  
Peter A Cattini
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Evolutionary Conservation ◽  
Chromosome 17 ◽  
N Gene ◽  
Interacting Protein ◽  
Physical Linkage ◽  
A Subunit ◽  
Polyadenylation Sites

The ubiquitously expressed rat BAF60b gene, which codes for a subunit of the multiprotein SWI/SNF complex, was recently identified between the pituitary growth hormone (GH-N) and thyroid hormone receptor interacting protein-1 (TRIP-1) genes. In primates, duplication of the GH-N gene has resulted in the addition of four placenta-specific (GH-V, CS-A, CS-B, and CS-L) genes downstream of the GH-N gene. As part of our study of the effect of remote sequences on the transcriptional regulation of the GH/CS gene family, we showed recently that these genes lie 40 kb upstream of the human TRIP-1 gene. We have now investigated the presence of the human BAF60b gene upstream of the TRIP-1 gene for evidence of evolutionary conservation of this arrangement or its disruption by the recent duplication of the nearby GH-N gene in primates. We report that, as in the rat genome, the human BAF60b gene is in the reverse transcriptional direction relative to the TRIP-1 gene, such that their polyadenylation sites are separated by 93 bp which compares with 92 bp in the rat. Reexamination of reported porcine TRIP-1 sequences also revealed the presence of the BAF60b gene separated by 93 bp, supporting an evolutionary conservation of this arrangement.Key words: P1 clone, gene mapping, downstream gene.

scholarly journals Differential involvement of nuclear factor-κB and activator protein-1 pathways in the interleukin-1β-mediated decrease of deiodinase type 1 and thyroid hormone receptor β1 mRNA

2006 ◽  
Vol 189 (1) ◽  
pp. 37-44 ◽  
Author(s):  
J Kwakkel ◽  
W M Wiersinga ◽  
A Boelen
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Nuclear Factor Κb ◽  
Hepatoma Cell Line ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activator Protein ◽  
Nfκb Pathway

One of the hallmarks of the sick euthyroid syndrome or non-thyroidal illness is a decrease of serum triiodothyronine, caused mainly by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines like interleukin (IL)-1β are likely involved in this disease, but are also known to inhibit thyroid hormone receptor (TR)-β1 gene expression, which is of interest as the D1 promoter contains TREs. The aim of the present study was to evaluate whether the IL-1β-induced decrease of D1 and TRβ1 mRNA is mediated by the same cytokine signalling pathways in a human hepatoma cell line (HepG2). We observed a downregulation of both D1 and TRβ1 mRNA after 4 h of incubating the cells with IL-1β. Sulfasalazine was used to inhibit the nuclear factor-κB (NFκB) pathway and SP600125, a chemical inhibitor of the c-Jun N-terminal kinase, was used as an inhibitor of the activator protein-1 (AP-1) pathway. AP-1 inhibition did not affect the decrease of D1 and TRβ1 mRNA, but the TRβ1 mRNA decrease was completely abolished after inhibiting NFκB, while D1 mRNA was unaffected. Only simultaneous inhibition of both the NFκB and AP-1 pathways abolished the D1 mRNA decrease. We concluded that IL-1β stimulation of HepG2 cells results in a marked decrease of D1 and TRβ1 mRNA. The decrease of TRβ1 mRNA is exclusively mediated by the NFκB pathway, while the decrease of D1 mRNA requires inhibition of both the AP-1 and the NFκB pathways.

scholarly journals E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

2020 ◽  
Vol 21 (22) ◽  
pp. 8515
Author(s):  
Manon Brunet ◽  
Claire Vargas ◽  
Dorian Larrieu ◽  
Jérôme Torrisani ◽  
Marlène Dufresne
Keyword(s):  
Thyroid Hormone ◽  
Ubiquitin Ligase ◽  
Hormone Receptor ◽  
Cell Cycle Progression ◽  
Thyroid Hormone Receptor ◽  
E3 Ubiquitin Ligase ◽  
Autism Spectrum ◽  
Causative Gene ◽  
Interacting Protein ◽  
C Terminus

The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications.

scholarly journals Nuclear Factor (NF)-κB-dependent Thyroid Hormone Receptor β1Expression Controls Dendritic Cell Function via Akt Signaling

2009 ◽  
Vol 285 (13) ◽  
pp. 9569-9582 ◽  
Author(s):  
Iván D. Mascanfroni ◽  
María del Mar Montesinos ◽  
Vanina A. Alamino ◽  
Sebastián Susperreguy ◽  
Juan P. Nicola ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Cell Function ◽  
Thyroid Hormone Receptor ◽  
Akt Signaling ◽  
Nuclear Factor ◽  
Dendritic Cell Function

scholarly journals Hepatocyte Nuclear Factor 4α Contributes to Thyroid Hormone Homeostasis by Cooperatively Regulating the Type 1 Iodothyronine Deiodinase Gene with GATA4 and Krüppel-Like Transcription Factor 9

2008 ◽  
Vol 28 (12) ◽  
pp. 3917-3931 ◽  
Author(s):  
Hiroto Ohguchi ◽  
Toshiya Tanaka ◽  
Aoi Uchida ◽  
Kenta Magoori ◽  
Hiromi Kudo ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Direct Role ◽  
Specific Expression ◽  
Iodothyronine Deiodinase ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Hormone Homeostasis

ABSTRACT Type 1 iodothyronine deiodinase (Dio1), a selenoenzyme catalyzing the bioactivation of thyroid hormone, is highly expressed in the liver. Dio1 mRNA and enzyme activity levels are markedly reduced in the livers of hepatocyte nuclear factor 4α (HNF4α)-null mice, thus accounting for its liver-specific expression. Consistent with this deficiency, serum T4 and rT3 concentrations are elevated in these mice compared with those in HNF4α-floxed control littermates; however, serum T3 levels are unchanged. Promoter analysis of the mouse Dio1 gene demonstrated that HNF4α plays a key role in the transactivation of the mouse Dio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4α site (direct repeat 1 [TGGACAAAGGTGC]; HNF4α-RE) is crucial for transactivation of the mouse Dio1 gene by HNF4α. Mouse Dio1 is also stimulated by thyroid hormone signaling, but a direct role for thyroid hormone receptor action has not been reported. We also showed that thyroid hormone-inducible Krüppel-like factor 9 (KLF9) stimulates the mouse Dio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4α-RE. Furthermore, KLF9 functions together with HNF4α and GATA4 to synergistically activate the mouse Dio1 promoter, suggesting that Dio1 is regulated by thyroid hormone in the mouse through an indirect mechanism requiring prior KLF9 induction. In addition, we showed that physical interactions between the C-terminal zinc finger domain (Cf) of GATA4 and activation function 2 of HNF4α and between the basic domain adjacent to Cf of GATA4 and a C-terminal domain of KLF9 are both required for this synergistic response. Taken together, these results suggest that HNF4α regulates thyroid hormone homeostasis through transcriptional regulation of the mouse Dio1 gene with GATA4 and KLF9.

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