Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ‐F1 homologue
2004; Springer Nature; Volume: 5; Issue: 6 Linguagem: Inglês
10.1038/sj.embor.7400147
ISSN1469-3178
AutoresKnut R. Steffensen, Elin Holter, Ann Båvner, Maria Nilsson, Markku Pelto‐Huikko, Stanislav I. Tomarev, Eckardt Treuter,
Tópico(s)Histone Deacetylase Inhibitors Research
ResumoScientific Report14 May 2004free access Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue Knut R Steffensen Knut R Steffensen Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Elin Holter Elin Holter Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Ann Båvner Ann Båvner Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Maria Nilsson Maria Nilsson Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Markku Pelto-Huikko Markku Pelto-Huikko Department of Developmental Biology, Tampere University Medical School, 33101 Tampere, Finland Department of Pathology, Tampere University Hospital, 33101 Tampere, Finland Search for more papers by this author Stanislav Tomarev Stanislav Tomarev Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, 20892-2730 USA Search for more papers by this author Eckardt Treuter Corresponding Author Eckardt Treuter Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Knut R Steffensen Knut R Steffensen Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Elin Holter Elin Holter Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Ann Båvner Ann Båvner Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Maria Nilsson Maria Nilsson Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Markku Pelto-Huikko Markku Pelto-Huikko Department of Developmental Biology, Tampere University Medical School, 33101 Tampere, Finland Department of Pathology, Tampere University Hospital, 33101 Tampere, Finland Search for more papers by this author Stanislav Tomarev Stanislav Tomarev Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, 20892-2730 USA Search for more papers by this author Eckardt Treuter Corresponding Author Eckardt Treuter Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden Search for more papers by this author Author Information Knut R Steffensen1,‡, Elin Holter1,‡, Ann Båvner1, Maria Nilsson1, Markku Pelto-Huikko2,3, Stanislav Tomarev4 and Eckardt Treuter 1 1Department of Biosciences at Novum, Karolinska Institutet, 14157 Huddinge, Sweden 2Department of Developmental Biology, Tampere University Medical School, 33101 Tampere, Finland 3Department of Pathology, Tampere University Hospital, 33101 Tampere, Finland 4Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, 20892-2730 USA ‡These authors contributed equally to this work *Corresponding author. Tel: +46 8 6089162; Fax: +46 8 7745538; E-mail: [email protected] EMBO Reports (2004)5:613-619https://doi.org/10.1038/sj.embor.7400147 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Nuclear receptors are master regulators of metazoan gene expression with crucial roles during development and in adult physiology. Fushi tarazu factor 1 (FTZ-F1) subfamily members are ancient orphan receptors with homologues from Drosophila to human that regulate diverse gene expression programs important for developmental processes, reproduction and cholesterol homeostasis in an apparently ligand-independent manner. Thus, developmental and tissue-specific cofactors may be particularly important in modulating the transcriptional activities of FTZ-F1 receptors. In Drosophila, the homeodomain protein Fushi tarazu acts as a cofactor for FTZ-F1 (NR5A3), leading to the hypothesis that a similar type of homeodomain cofactor–nuclear receptor relationship might exist in vertebrates. In this study, we have identified and characterized the homeodomain protein Prox1 as a co-repressor for liver receptor homologue 1 (LRH1/NR5A2), a master regulator of cholesterol homeostasis in mammals. Our study suggests that interactions between LRH1 and Prox1 may fulfil roles both during development of the enterohepatic system and in adult physiology of the liver. Introduction Nuclear receptors (NRs) are master regulators of metazoan gene expression programmes governing crucial processes during development and in adult physiology. Whereas ligand-binding may primarily trigger transcriptional responses of ligand-activatable receptors, the action of tissue-specific or developmental cofactors may have equally important roles, particularly in the case of orphan receptors where ligand binding is uncertain or can be excluded (Li et al, 2003). Members of the Fushi tarazu factor 1 (FTZ-F1, NR5A3) subfamily belong to the category of ancient orphan receptors with homologues from Drosophila to human. Mammalian homologues include steroidogenic factor 1 (SF1/NR5A1), which regulates reproductive development and steroidogenesis (Hammer & Ingraham, 1999), and liver receptor homologue 1 (LRH1/NR5A2), which regulates cholesterol homeostasis in the enterohepatic system by modulating the expression of genes encoding enzymes involved in bile acid synthesis, bile salt circulation and reverse cholesterol transport (Francis et al, 2003). Recent structure–function analysis indicates that the LRH1 ligand-binding domain (LBD) adopts an active conformation in the absence of ligand binding and that the coregulator-binding surface may not be optimized for common cofactors (Sablin et al, 2003). Whereas MBF1 (Brendel et al, 2002) and TIF2 (Sablin et al, 2003) may act as coactivators, the orphan receptor SHP (NR0B2) fulfils specific roles as an inducible co-repressor in the feedback regulation of LRH1 target genes involved in bile acid synthesis (Goodwin et al, 2000; Lu et al, 2000). Other cofactors might be particularly relevant for LRH1 activity regulation during development and under circumstances where SHP is insufficient or unavailable, for example under normal dietary conditions in liver. Previous studies in Drosophila had identified the homeodomain protein Fushi tarazu (FTZ) as a developmental cofactor (Guichet et al, 1997; Yu et al, 1997), which was subsequently demonstrated to interact with LRH1 (Schwartz et al, 2001). As there are no FTZ homologues in vertebrates, functionally related homeodomain proteins may replace its function. Recently, the homeodomain protein Prox1 was demonstrated to interact with FTZ-F1 homologues in zebrafish and, in particular, to cooperate in vivo with FF1b (the SF1 homologue) during the development of the inter-renal primordium (Liu et al, 2003), raising the possibility that Prox1 may act as a cofactor in mammals as well. In this study, we describe the identification of Prox1 as a co-repressor for LRH1. Characteristics of this interaction as well as overlapping expression patterns and developmental functions suggest that the relationship between LRH1 and Prox1 might be particularly important in regulating gene expression patterns during mammalian liver and pancreas development and in adult physiology of the enterohepatic system. Results Characterization Of Prox1–LRH1 Interactions NR-interacting proteins that had been identified in previous two-hybrid screenings (Johansson et al, 1999) were tested for interactions with LRH1 in a yeast two-hybrid growth assay. Strong interactions were observed with the homeodomain protein Prox1, an uncharacterized candidate cofactor. Interactions of Prox1 or SHP (for comparison) with LRH1 variants were quantified using liquid β-galactosidase assays (Fig 1A) and revealed that the minimal LBD (Sablin et al, 2003) was sufficient for interaction and also necessary, as no interaction was observed after deleting helix 12 (data not shown). Prox1 domain mapping and mutagenesis (Fig 1B) revealed that interactions with LRH1 required an N-terminal region containing two putative NR boxes, with NR1 (consensus LxxLL motif) being more important than NR2 (non-consensus IxxLL motif). The critical involvement of both NR boxes in determining the interactions of Prox1 with LRH1 was directly confirmed in mammalian reporter assays (see below and supplementary Fig 2 online). Figure 1.Yeast two-hybrid analysis of LRH1 interactions with Prox1. (A) Gal4-LRH1 variants were tested for interaction with GAD-Prox1 (aa 48–337) or SHP (aa 1–260). The schematic LRH1 domain structure highlights DNA-binding domain (DBD), LBD and transcription regulation functions (AFH, AF2). (B) GAD-Prox1 variants were tested for interaction with Gal4-LRH1 (aa 192–560). The schematic Prox1 domain structure highlights putative NR-boxes 1 and 2 and the DNA-binding/regulatory domain (homeo/pros). Download figure Download PowerPoint These findings and the direct character of LRH1–Prox1 interactions were supported by in vitro binding studies using purified glutathione S-transferase (GST)–LRH1 protein and radiolabelled Prox1 fragments (Fig 2A). Whereas the N-terminal fragments spanning the NR-box 1/2 domain bound well to LRH1, no binding was observed with two C-terminal fragments spanning the homeo-prospero domain including an LxxLL motif that apparently does not have any role in high-affinity LRH1 binding. Finally, coexpression of green fluorescent protein (GFP)–Prox1 and LRH1 in mammalian cells resulted in the relocalization of LRH1 from a uniform pattern (Fig 2B, panel I) to specific Prox1-containing nuclear structures (Fig 2B, panel II). We conclude that LRH1 and Prox1 do interact in yeast, in mammalian cells and in vitro, and that these interactions require LRH1 amino-acid (aa) residues 317–560, that is, the entire LBD, and Prox1 aa residues 48–132 containing two NR-box motifs. Figure 2.Characterization of LRH1 and Prox1 interactions. (A) GST pull-down analysis. Binding of 35S-methionine-labelled Prox1 fragments to GST–LRH1 (aa 192–560) or GST alone was analysed. Input represents 20% of the material used for the pull-down. (B) Intracellular localization analysis. GFP-tagged Prox1 and VP16-tagged LRH1 (0.5 μg plasmid) were expressed individually (panel I) or coexpressed (panel II) in Cos7 cells and visualized directly or indirectly using anti-VP16 antibody. Representative fluorescence images for Prox1 (green), for LRH1 (red) and merged images (yellow) following superimposition are shown. Download figure Download PowerPoint Expression Pattern Of Prox1 And Lrh1 We next estimated relative mRNA expression levels in human tissues, and found that Prox1 and LRH1 are highly expressed in the liver and pancreas and at lower levels also in the ovary and small intestine (Fig 3A). Furthermore, a splicing variant (3.5 kb) of the Prox1 mRNA is seen in the testis, which is interesting as testis is a target tissue of SF1. To demonstrate the expression of Prox1 and LRH1 in the adult liver, immunohistochemistry revealed that both proteins are present in virtually all hepatocyte nuclei (Fig 3B). These results were confirmed by in situ hybridization showing strong signals for both LRH1 and Prox1 mRNA in hepatocytes (supplementary Fig 1 online). In summary, our data suggest that Prox1 is expressed in all LRH1 target tissues and is probably a physiologically relevant cofactor of LRH1, particularly in the adult liver of mammals. Figure 3.Tissue distribution and cellular coexpression of LRH1 and Prox1 in the liver. (A) Human multiple tissue northern blots containing 2 μg of poly(A)+ mRNA from each tissue were probed successively with 32P-labelled LRH1, Prox1 and β-actin cDNAs. RNA molecular weights are in kilobases. (B) Adult mice liver samples were subjected to immunohistochemistry as described in Methods. Representative fluorescence images for Prox1 (red) and for LRH1 (green) are shown in panel I. Corresponding tissue samples without staining are shown in panel II. Download figure Download PowerPoint Inhibition Of Lrh1 Activity By Prox1 The effect of Prox1 on LRH1 transcriptional activity was analysed in a number of different experimental settings (Fig 4) using the shp promoter, an established LRH1 target (Lu et al, 2000). First, we found that LRH1 activation of the shp-luc reporter in Cos7 cells was repressed by coexpression of Prox1 (Fig 4A). Repression by Prox1 was as effective as repression by SHP (Fig 4A) at equal expression levels as judged from immunoblots (data not shown). Importantly, repression was not simply due to squelching as an equally expressed NR-box 1/2 mutant Prox1 did not repress (supplementary Fig 2 online), further confirming the importance of the N-terminal NR boxes 1 and 2 in determining Prox1–LRH1 interactions (Fig 1B). Second, transfections of the HuH7 human liver cell line revealed that Prox1 and the p160 coactivator TIF2 effectively antagonized each other on the shp promoter in a dose-dependent manner (Fig 4B). Third, LRH1 overexpression increased endogenous SHP mRNA levels in HuH7 cells, whereas Prox1 coexpression antagonized this increase (Fig 4C). Fourth, decreasing endogenous Prox1 expression by RNA interference revealed that Prox1-specific but not control short interfering RNA (siRNA) increased LRH1-dependent reporter activity (Fig 4D). These results collectively suggest a co-repressor function of Prox1. Figure 4.Effects of Prox1 on LRH1 activity. (A) Effect of Prox1 on LRH1-dependent reporter gene activity. Cos7 cells received 100 ng shp-luc reporter, 100 ng pSG5-LRH1, 200 ng pFlag-Prox1 or 200 ng pFlag-SHP plasmid as indicated, and luciferase activities were related to the activity of the reporter in the absence of exogenous LRH1, Prox1 and SHP, which was set to 100%. (B) Effect of Prox1 on TIF2 coactivation of LRH1-dependent reporter gene activity. HuH7 cells received 500 ng of the shp-luc reporter, 200 ng of pSG5-LRH1, 200/400/1,000 ng (1:1/1:2/1:5) of pFlag-Prox1 and 200/400/1,000 ng (1:1/1:2/1:5) of pSG5-TIF2 as indicated. Luciferase activities were related to the activity of the reporter alone, which was set to 1. (C) Effect of Prox1 on the expression of endogenous SHP mRNA. HuH7 cells received 200 ng pSG5-LRH1 and/or 1,800 ng pFlag-Prox1 as indicated. Expression levels of endogenous SHP cDNA in the presence of exogenous LRH1 and/or Prox1 were related to the levels in their absence (control), which was set to 100%. (D) Effect of reducing endogenous Prox1 levels by RNA interference on reporter activity. HuH7 cells received 500 ng shp-luc, 100 ng pSG5-LRH1, 10 μl Prox1 siRNA duplex oligos (20 μM) or 10 μl control siRNA (20 μM) as indicated. Luciferase activities of the co-transfections were related to the activity of the reporter alone, which was set to 1. All individual experiments (A–D) were performed with equal amounts of DNA by filling up with the respective empty vector. Download figure Download PowerPoint Intrinsic Transcriptional Features Of Prox1 Experiments were carried out to investigate whether or not Prox1 would directly repress transcription and, if so, which cofactors target the putative repressor function and may act in concert with Prox1? First, analysis of Prox1 variants, in comparison to the two established repressors SHP and thyroid hormone receptor (TR)α, in a repressor assay clearly revealed that Prox1 can act as a strong transcriptional repressor (Fig 5), Domain mapping revealed the existence of an N-terminal potent repressor domain (aa 108–337), whereas the C-terminal homeo-prospero domain (aa 544–736) was not required for Prox1 repression and had only a weak repressor potential on its own. Figure 5.Analysis of Prox1 repression. (A) Schematic Prox1 domain structure and repressor constructs. (B) Repressor assay. Gal4-tagged expression constructs for Prox1, SHP and TRα (each 400 ng plasmid) were analysed for repression of a luc reporter (500 ng plasmid) containing a complex promoter with activator (HNF1-VP16)- and repressor (Gal4 fusion protein)-binding sites (Båvner et al, 2002). Download figure Download PowerPoint Assuming histone deacetylases as potential cofactors involved in Prox1 repression, we investigated whether various class I and II HDACs (Fig 6A and data not shown) would change their localization pattern upon coexpression with GFP–Prox1 or vice versa. HDAC3 was clearly identified as a candidate Prox1 partner, whereas HDAC2 did not colocalize (Fig 6A). The direct character of HDAC3 interactions was further supported by GST pull-down assays (Fig 6B). HDAC3 was specifically retained by a Prox1 fragment containing the repressor domain but not by the non-repressing homeo-prospero domain or by GST alone. Finally, endogenous Prox1–HDAC3 complexes were detected by co-immunoprecipitation from HuH7 cell extracts (Fig 6C). We conclude that Prox1 has intrinsic transcriptional repression potential that is largely dependent on an N-terminal repression domain and that may involve recruitment of HDAC3. Figure 6.Characterization of Prox1 interactions with HDAC3. (A) Intracellular localization analysis. GFP-tagged Prox1 and Flag-tagged HDACs (0.5 μg plasmid) were expressed individually (panel I) or coexpressed (panel II) in Cos7 cells and visualized directly or indirectly using anti-Flag antibody. Representative fluorescence images for HDACs (red) and Prox1 (green) are shown. Merged images (yellow) following superimposition depict colocalization in the case of HDAC3. (B) GST pull-down assay. Binding of 35S-methionine-labelled HDAC3 to GST–Prox1 IAD (aa 48–337), GST–Prox1 HP (aa 544–736) or GST alone was analysed. Input (In) corresponds to 20% of the material subjected to the pull-down. (C) Co-immunoprecipitation of endogenous Prox1 and HDAC3. Immune complexes from HuH7 whole-cell extracts (300 μg total protein) were isolated using HDAC3 antibody or using Gal4 antibody (control). Precipitates were analysed using a rabbit polyclonal Prox1-specific antibody. The input (In) corresponds to 20% of the material subjected to immunoprecipitation. (*) Nonspecific band; (IgG) position of the immunoglobulin heavy chain (approximately 55 kDa). Download figure Download PowerPoint Discussion A number of independent studies indicate that Prox1 and LRH1 are coexpressed throughout development of endoderm-derived tissues including liver, pancreas and intestine in mice and humans (Oliver et al, 1993; Galarneau et al, 1996; Tomarev et al, 1996; Rausa et al, 1999; Burke & Oliver, 2002). Functional inactivation of the mouse Prox1 gene caused embryonic lethality due to multiple developmental defects, including abnormal cell proliferation and migration during liver morphogenesis (Sosa-Pineda et al, 2000). Expression of LRH1 is evident in the same tissues of adult mammals, for example, in liver hepatocytes and bile ducts and exocrine pancreas (Galarneau et al, 1996; Annicotte et al, 2003). Although we were able to demonstrate coexpression of Prox1 with LRH1 in mouse liver, the specific roles of Prox1 in adult physiology of liver, pancreas, testis and ovary and particularly its relationship to relevant LRH1 cofactors such as SHP or DAX-1 in these tissues remain to be elucidated. One hypothesis could be that, for example in liver, Prox1 may modulate LRH1 target gene expression during development and under normal physiological conditions, whereas SHP may primarily serve as a metabolic sensor under conditions of increased metabolic activity such as high-cholesterol diet. The negative effect of Prox1 on LRH1 (this study) and SF1 (Liu et al, 2003) seen in cell culture systems may be physiologically significant, as it is currently unclear whether LRH1 acts as an activator of target gene transcription in vivo. A recent study highlights this issue by demonstrating that heterozygous LRH1 knockout mice express unexpectedly fivefold to sevenfold higher levels of CYP7A and CYP8B genes than wild-type mice (Del Castillo-Olivares et al, 2004). It is conceivable that co-repressors such as Prox1 may actually be particularly important to suppress 'constitutively' active NRs including LRH1, whereas a majority of NRs would not require Prox1-like co-repressors in the absence of activating ligands. Despite extensive work aimed at understanding Prox1 function, little is currently known about its direct molecular targets, that is, regulated genes and regulatory proteins. Thus, LRH1 represents one of the first target factors of Prox1 action. Further, the characterization of Prox1 as a potent repressor of transcription and the possible connection to HDAC3 is particularly interesting, as this deacetylase is a component of a conserved co-repressor complex involved in repression by NRs (Heinzel et al, 1997). Whereas future work has to dissect the mechanisms of Prox1 co-repressor action, we found that LRH1 activity is increased by trichostatin A (A.B. and E.T., unpublished data), consistent with a role of HDACs in modulating LRH1 activity. Many homeodomain proteins act both as transcriptional activators and repressors in a context-dependent manner, so alternative mechanisms of repression or activation have to be considered for Prox1 as well. The ability of Prox1 to modulate mammalian gene expression patterns by acting as a cofactor for LRH1 and perhaps other NRs is probably a characteristic of all vertebrates, as Prox1 was recently demonstrated to cooperate with FF1b (SF1/NR5A1) during the development of the inter-renal primordium in zebrafish (Liu et al, 2003). Intriguingly, the principle of a homeodomain protein acting as a transcriptional coregulator for FTZ-F1 members is evolutionarily conserved as this relationship resembles Drosophila FTZ-F1/FTZ, which is a developmental homeodomain protein unique to flies and one of the earliest characterized LxxLL coregulators (Guichet et al, 1997; Yu et al, 1997; Schwartz et al, 2001). Thereby, the identification of mammalian Prox1 as an LRH1 coregulator fulfils the original proposal that '…interactions of this sort might allow homeodomain proteins to modulate the activity or target range of nuclear hormone receptors' and '…that other NR–homeodomain protein interactions may be important and common in developing organisms' (Guichet et al, 1997). Methods Plasmids/oligonucleotides Plasmid constructs were generated using standard cloning procedures and verified by restriction enzyme analysis and DNA sequencing. Site-directed mutagenesis was performed using the QuickChange site-directed mutagenesis kit (Stratagene). Details are available on request. Protein–protein interaction assays Experimental conditions of yeast two-hybrid assays, GST pull-down assays, intracellular localization analysis and co-immunoprecipitations are essentially as described previously (Johansson et al, 1999; Båvner et al, 2002; Holter et al, 2002) and are provided as supplementary information online. Analysis of mRNA and protein expression Human multiple tissue northern blots (MTN blot #7760-1 and 7759-1, Clontech) were hybridized for 1 h with probes against human Prox1, human LRH1 and human β-actin according to the manufacturer's instructions. In situ hybridization and immunohistochemistry procedures are given as supplementary information. Cell cultures and transient transfections Cell culture: Human hepatoma HuH7 and monkey kidney Cos7 cells were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. Reporter assays: Cells were plated in six-well plates and transiently transfected using Lipofectamine 2000 (Life Technologies) and incubated for 24 h. Relative luciferase units (RLU) represent the mean±s.d. of duplicate transfections and were reproduced in independent experiments. RNA interference: Transfection of siRNA duplexes was performed in HuH7 cells using Lipofectamine 2000. siRNA sequences are given as supplementary information online. mRNA extraction and quantification by real-time PCR Total RNA from cell cultures was isolated using the RNeasy mini-kit (Qiagen). A 0.5 μg portion of RNA was treated with DNase I (Invitrogen) and subsequently transcribed into cDNA by Superscript II (Invitrogen). mRNA expression was quantified by Taqman (SHP) or SYBRgreen (18S; internal standard) qPCR on an ABI 7700 machine (Applied Biosystems). Supplementary information is available at EMBO reports online (http://www.nature.com/embor/journal/vaop/ncurrent/extref/7400147-s1.pdf) Acknowledgements We thank Dr J. Auwerx, Dr C. Dreyer, Dr M. Lazar, Dr S. Schreiber, Dr C. Grozinger, Dr E. Verdin and Dr T. Kouzarides for providing plasmids and reagents. We thank members of the Nuclear Receptor Biology Unit at Novum, particularly Sabyasachi Sanyal, for sharing materials and ideas and Ulla-Margit Jukarainen for excellent technical assistance. This work is supported by grants from the Swedish Research Council (E.T.), the Swedish Society for Medical Research, the Swedish Cancer Society and the Medical Research Fund of Tampere University Hospital (M.P.-H.). 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