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Transcriptional Activity by an HNF-1ß Missense Mutant Associated with Type 5 Maturity-Onset Diabetes of the Young with Hepatic and Biliary Manifestations
Department of Pediatrics (S.K., Y.M., Y.H., T.I.), Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655; and Japan Health Sciences Foundation (S.K.), Tokyo 103-0001, Japan
Address all correspondence and requests for reprints to: Sachiko Kitanaka, M.D., Ph.D., Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: sachi-tky{at}umin.ac.jp.
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Abstract |
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and regulates various target genes. HNF-1ß mutations are rare, and no functional analysis has been performed in conjunction with HNF-1. HNF-1ß is expressed in the liver and biliary system and controls liver-specific and bile acid-related genes. Moreover, liver-specific Hnf-1ß knockout mice present with severe jaundice. However, no patients with HNF-1ß mutations have biliary manifestations. In this report, we found a novel missense mutation in the HNF-1ß gene in a patient with neonatal cholestasis and liver dysfunction together with the common features of MODY5. Functional analysis revealed that the mutant HNF-1ß 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-1ß and inhibited its DNA binding. Moreover, the mutant had a promoter- and cell-specific transcriptional repressive effect on HNF-1 and a promoter-specific inhibitory effect on HNF-1 DNA binding. From these results, we considered that the different phenotype of patients with HNF-1ß mutations might be caused by the different HNF-1ß activity in conjunction with the different repression of HNF-1 activity in selected promoters and tissues. |
Introduction |
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HNF-1ß is closely related to HNF-1, a gene heterozygously mutated in MODY3 (6). HNF-1 and HNF-1ß were initially identified as nuclear proteins binding to an element required for liver-specific gene transcription (7, 8). HNF-1 and HNF-1ß bind to the same consensus HNF-1 site and function as homodimers or heterodimers to regulate the expression of target genes. The transcriptional modification by the coexpression of HNF-1 and HNF-1ß has not been well studied but is known to differ by promoters. In some promoters, HNF-1ß has no additional transcriptional effect on HNF-1, whereas it represses HNF-1 in other promoters (8, 9, 10). Considered together with the changes in the ratio of HNF-1ß expression to HNF-1 during development, it was suggested that HNF-1ß has a regulatory role in the HNF-1/1ß target gene regulation (9, 10, 11). Until now, the transcriptional activities of only seven of the 12 HNF-1ß mutants found in MODY5 patients have been analyzed; some mutants have a loss of transcriptional activity, and some are activated (5, 12, 13, 14, 15). However, none of the HNF-1ß mutants was analyzed in conjunction with HNF-1, and it is not known how these HNF-1ß mutants have transcriptional effects on HNF-1.
HNF-1ß is expressed in embryonic gall bladder and intrahepatic bile ducts (16). It is also expressed in embryonic and adult liver. Recently, HNF-1ß has been shown to be important in bile system morphogenesis, using conditional knockout mice (17). These mice presented with severe jaundice caused by abnormalities of the gall bladder and intrahepatic bile ducts. It has also been shown that HNF-1ß and HNF-1 control genes involved in bile acid transport and metabolism (17, 18). However, to date, no patients with HNF-1ß mutations had biliary manifestation, and only a few patients had mild liver dysfunction (19, 20).
In this article, we report a patient with a novel HNF-1ß mutation. The patient had neonatal cholestasis and liver dysfunction together with diabetes mellitus and renal cysts. Analysis of the transcriptional activity using different promoters and different cell lines revealed that the mutant HNF-1ß had diminished transcriptional activity with a promoter-specific dominant-negative effect on wild-type HNF-1ß. Moreover, we found that the mutant HNF-1ß repressed the activity of HNF-1 in a promoter- and cell-specific manner. We consider that the difference in the phenotype of patients with HNF-1ß mutation is, in part, related to such a difference in the promoter- and tissue-specific effect of HNF-1ß in conjunction with HNF-1.
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Subjects and Methods |
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The proband is the second child of nonconsanguineous Japanese parents. He was born light-for-date (39 wk, 2390 g) and had respiratory distress that needed transient respiratory support. He had hyperbilirubinemia (direct bilirubin dominant) and white stools at neonatal period (Table 1
). However, open cholangiography showed no abnormality of the biliary duct. Histological examination of the liver revealed marked cholestasis, decreased number of the intrahepatic bile ducts (not severely decreased as in Allagile syndrome), and no signs of infiltration. Hypercholesterolemia was also noted, which normalized thereafter. His jaundice improved spontaneously by 9 months of age. However, his serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were constantly high (Table 1). Serum antibodies for various viruses were negative. The etiology of his cholestasis and liver dysfunction remained unknown. His speech development was slightly delayed.
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). Renal echography revealed multiple bilateral cysts (right, four cysts of 1–2 cm diameter; left, one cyst of 1 cm diameter). A renogram suggested mild renal insufficiency.
Many of his paternal family members had a history of nonviral liver dysfunction and renal insufficiency (Fig. 1). The grandfather (I-1) and an aunt (II-1) died from hepatic cancer and liver cirrhosis. His father (II-3) and his uncle (II-5) had liver dysfunction of unknown etiology. Two paternal aunts (II-1 and II-2) had history of renal insufficiency. However, because we could not contact the father and other family members, the clinical details could not be obtained. The neonatal histories of the paternal family members were also unknown. His paternal grandmother (I-2) was diagnosed with non-insulin-dependent diabetes mellitus at age 60 yr. No other family members had overt diabetes, although no examination, including oral glucose tolerance test, was performed, except for his mother (II-4) who had a normal glucose response.
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DNA amplification and sequence analysis of the HNF-1ß gene
Genomic DNA was isolated from the peripheral white blood cells. PCR was performed to amplify the entire coding region and exon-intron boundaries of the HNF-1ß gene (exons 1–9) using sequence-specific primers (21). All the exons were amplified in a PCR thermocycler (Applied Biosystems, Foster City, CA) by initial denaturation at 95 C for 9 min, followed by 30 cycles at 95 C for 30 sec, 57 C for 30 sec, and 72 C for 30 sec using AmpliTaq Gold (Applied Biosystems) (22). The corresponding PCR products were purified and sequenced directly in both directions. A mutation in exon 2 was confirmed by cloning the PCR product into the vector pCR2.1-TOPO (Invitrogen Corp., Carlsbad, CA) and sequencing the clones derived from both alleles.
Restriction analysis
A mutation found in exon 2, which creates a HinfI restriction site, was confirmed by the digestion of PCR products with the restriction enzyme. The PCR products from 60 healthy Japanese volunteers were similarly analyzed to exclude a polymorphism of the gene.
Construction of plasmids
The constructs of wild-type HNF-1ß expression plasmid pCMV-1ßWT and HNF-1 expression plasmid pCMV-1 in pCMV6b were described previously (12). An H153N mutation in HNF-1ß was introduced with a Quick Change Site-directed mutagenesis kit (Stratagene, La Jolla, CA). Each of the wild-type and mutant cDNA was subcloned into the BamHI/EcoRI site of pcDNA3 (Invitrogen) for in vitro translation. The construction of the luciferase reporter plasmid with human glucose transporter-2 (GLUT2) promoter region and the construction with five copies of the rat insulin I gene mini-enhancer element E2A3/4 (Far1/FLAT) were described previously (12, 23).
Cell transfection and luciferase assay
COS-7 cells, HepG2, and HeLa cells were maintained in DMEM supplemented with 10% fetal bovine serum. Cells cultured in six-well plates were transfected with 250 ng of DNA, including 100 ng of the reporter gene, the indicated amounts of each HNF-1 expression plasmids, and 0.5 ng of pRL-CMV (Promega, Madison, WI) using LipofectAMINE PLUS (Invitrogen) according to the manufacturer’s protocol. After 24 h, the transcriptional activity was assayed using a Dual-Luciferase Reporter Assay System (Promega).
For Western blot analysis, the transfected cells were collected and were subjected to lysis in the lysis buffer (25 mM Tris-HCl, pH 7.6; 50 mM NaCl; 2% Nonidet P-40; 0.5% deoxycholate; and 0.2% sodium dodecyl sulfate). After determination of protein concentrations, equal amounts of cell lysates, adjusted by Renilla activity for each cell line, were separated by SDS-PAGE, transferred to a nitrocellulose membrane, and blotted with a primary antibody against HNF-1ß (goat polyclonal; Santa Cruz Biotechnology, Santa Cruz, CA) and, subsequently, with a horseradish peroxidase-conjugated secondary antibody (Sigma, St. Louis, MO). Blot was visualized by enhanced chemiluminescence (ECL; Amersham Biosciences, Piscataway, NJ).
In vitro translation and EMSA analysis
Wild-type HNF-1ß, HNF-1, and mutant HNF-1ß proteins were synthesized with pcDNA3–1ßWT, pcDNA3–1, and pcDNA3–1ßH153N using the TNT T7 Coupled Reticulocyte Lysate System (Promega). Equivalent amounts of proteins, as determined by SDS-PAGE and autoradiograhy of [35S]methionine-labeled proteins, were incubated in a 20-µl reaction containing 10 mM Tris-HCl (pH 7.5), 1 mM dithiothreitol, 1 mM EDTA, 10% glycerol, 1 mM MgCl2, 2 µg polydeoxyinosinic deoxycytidylic acid, 30 mM (for GLUT2) or 75 mM (for E2A3/4) of KCl, and 40,000 cpm of 32P-labeled double stranded oligonucleotides. The sequences of the oligonucleotides were as follows: GLUT2, 5'-AAGACCTCAGTAAAGATTAACCATCATTA-3'; and insulin mini-enhancer E2A3/4, 5'-CTTCATCAGGCCATCTGCCCCTTGTTAATAATCTAATTACCCTAGGTCTA-3'. The DNA-protein complexes were resolved on a 5% nondenaturing polyacrylamide gel in 0.5x Tris-borate, EDTA buffer. The gel was then dried and exposed to x-ray film for autoradiography.
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Results |
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The patient had neonatal cholestasis, liver dysfunction, diabetes mellitus, renal insufficiency, and renal cysts. There was no known syndrome with such complications, so we first investigated the HNF-1ß gene, the abnormality of which is known to cause diabetes mellitus and renal cysts. All the PCR products of the nine exons of HNF-1ß gene were sequenced directly, revealing a heterozygous mutation in exon 2. This C to A transition in the first nucleotide in codon 153 resulted in the substitution of histidine to asparagine (H153N). This heterozygous mutation was confirmed by repeated PCR and sequencing in both directions, as well as by sequencing the subcloned PCR products and by restriction analysis. No mutation was found in the exons and exon-intron boundaries of the HNF-1 gene.
H153 is highly conserved among human, mouse, and rat HNF-1ß/HNF-1. It is suggested from the crystal structure of HNF-1 that H153 (corresponds to H147 in HNF-1) is located in the fourth helices of the POU-specific domain (24). H147 substitutions in HNF-1 are predicted to disrupt DNA recognition indirectly through perturbations in local environment. Thus, H153 may be quite an important amino acid for HNF-1ß function, especially for DNA binding.
This missense mutation can be detected by the restriction enzyme HinfI, which recognizes the mutant allele. HinfI digestion of the exon 2 PCR products amplified from the patient produced three fragments, indicating that the patient was heterozygous for the mutation (data not shown). Restriction fragment length polymorphism analysis on 60 healthy volunteers revealed no mutation, indicating that H153N mutation is not a common DNA sequence polymorphism (data not shown).
The restriction fragment length polymorphism analysis revealed the subject’s mother to be normal. This result indicates that the mutation in the patient may be derived from his father or may be a de novo mutation. Analysis of his father and other family members could not be performed because informed consent was not obtained. Therefore, the cosegregation of this mutation with the clinical manifestations remains unknown.
Effect of the H153N mutation on HNF-1ß function and DNA binding
To examine whether the H153N mutation affects the transcriptional activity of HNF-1ß, wild-type and mutant HNF-1ß were transiently overexpressed in mammalian cells, and the transcriptional activity was analyzed by luciferase reporter assay. Because the missense mutation is located in the region involved in DNA binding and is suspected of having different activities according to the sequence of the HNF-1 sites, we analyzed the transcriptional activities in different promoters. We used the promoter of the human gene for GLUT2, which mediates glucose transport, and a mini-enhancer of the rat insulin I gene, E2A3/4 (Far/FLAT) sequence, both of which are known to be bound and transactivated by HNF-1 (12, 25). We also used different cell lines including liver-derived HepG2 cells and kidney-derived COS-7 cells. Transfection of the wild-type HNF-1ß efficiently increased both reporter gene activity in both HepG2 cells and COS-7 cells (Fig. 2, A–D). However, the mutant had negligible transcriptional activity using both reporter genes in HepG2 cells (Fig. 2, A and B). Similar results were also observed in HeLa cells (data not shown). On the other hand, in COS-7 cells, the mutant showed weak but significant transcriptional activity using both reporter genes at a higher level of transfection (Fig. 2, C and D). Using Western blot analysis of the transfected cells, we confirmed that the mutant protein was apparently expressed in these cells (Fig. 2E).
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). EMSA showed that wild-type HNF-1ß protein bound to both the insulin mini-enhancer element and consensus cis-element for HNF-1/1ß in the human GLUT2 promoter (Fig. 3, B and C, lane 2). The binding could be blocked by the addition of a 100-fold excess of each unlabeled oligonucleotide (Fig. 3, B and C, lane 3). However, the mutant protein did not bind to either oligonucleotide (Fig. 3, B and C, lane 4), even at an increased dose (data not shown).
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Dominant-negative effect of the H153N mutant on wild-type HNF-1ß
Because this patient was heterozygous for the H153N mutation, we next examined whether this mutant had a dominant-negative effect on wild-type HNF-1ß. Wild-type HNF-1ß was transfected with increasing amounts of the H153N mutant in HepG2 cells. The transcriptional activity of the wild-type HNF-1ß was significantly inhibited by H153N using the insulin mini-enhancer reporter (Fig. 4A). On the other hand, no inhibition was observed using the GLUT2 promoter (Fig. 4B). Similar results were obtained in COS-7 and HeLa cells (data not shown).
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, compare lane 7 with lane 2). This result was compatible with the transactivation study, in which H153N showed an inhibitory effect on wild-type HNF-1ß (Fig. 4A). On the other hand, in the GLUT2 promoter sequence, an excess amount of the H153N mutant did not inhibit but rather enhanced HNF-1ß binding (Fig. 3C, compare lane 7 with lane 2). Because the size of the mutant protein is indistinguishable from the size of the wild-type protein, this enhancement might involve a wild-type/H153N heterodimer. From these results, it is indicated that H153N mutant has a promoter-specific inhibitory effect on wild-type HNF-1ß DNA binding and a promoter-specific dominant-negative effect on wild-type HNF-1ß transcriptional activity.
Effect of HNF-1ß H153N on the HNF-1 transcriptional activity and DNA binding
Because HNF-1ß forms a heterodimer with HNF-1 and binds to the same target elements, we further investigated the effect of HNF-1ß H153N mutation on HNF-1 transcriptional activity. HNF-1 alone had transcriptional activity approximately 1.5–2 times that of HNF-1ß on these promoters, and we used an HNF-1 DNA dose that showed intermediate activity in the dose-dependent curves (data not shown). In HepG2 cells, wild-type HNF-1ß had dose-dependent additional transcriptional activity on HNF-1 (Fig. 5A). In contrast, the H153N mutant significantly repressed the activity of HNF-1 in a dose-dependent manner, using an insulin mini-enhancer reporter (Fig. 5A). A similar repressive effect was also observed in COS-7 cells (data not shown). The repression of HNF-1 by H153N mutant was more remarkable (approximately 95% repression at maximum) in HeLa cells, in which wild-type HNF-1ß had a repressive effect (Fig. 5C). On the other hand, using a GLUT2 promoter in which wild-type HNF-1ß showed additional transactivity on HNF-1, the H153N mutant had no significant effect on HNF-1 activity in both HepG2 cells (Fig. 5B) and HeLa cells (data not shown).
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DNA binding by EMSA. HNF-1 and wild-type HNF-1ß bound as either homodimers or heterodimers on both the insulin mini-enhancer and GLUT2 reporters (Fig. 6, A and B, lanes 2–4). The binding of HNF-1ß seemed to be weaker to the GLUT2 promoter sequence than to the insulin mini-enhancer element (Fig. 6, A and B, lane 3). In the insulin mini-enhancer element, the addition of the H153N mutant to HNF-1 showed an inhibition of HNF-1 homodimer binding (Fig. 6A compare lanes 6, 7 with lane 2). On the other hand, in the GLUT2 promoter sequence, the addition of the H153N mutant showed no inhibition of HNF-1 homodimer binding (Fig. 6B, lanes 6, 7).
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, and the repressive effect might be exerted through the inhibition of the DNA binding of HNF-1.
Effect of HNF-1ß H153N on the HNF-1/HNF-1ß transcriptional activity and DNA binding
Because the patient possesses HNF-1 and wild-type HNF-1ß together with an HNF-1ß H153N mutant, the effect of the H153N mutant on the HNF-1/HNF-1ß heterodimer was further examined. An increasing amount of the H153N mutant was cotransfected with HNF-1 and wild-type HNF-1ß in HepG2 cells. The H153N mutant repressed the HNF-1/HNF-1ß heterodimer activity using the insulin mini-enhancer reporter, whereas it had no effect using the GLUT2 promoter (Fig. 7, A and B). Similar results were obtained in COS-7 and HeLa cells (data not shown). This promoter-specific repressive effect was consistent with the independent effects on HNF-1ß (Fig. 4) and HNF-1 (Fig. 5).
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/HNF-1ß heterodimer DNA binding was further analyzed by EMSA. In the insulin mini-enhancer element, the addition of the H153N mutant inhibited HNF-1/HNF-1ß heterodimer binding (Fig. 6A, compare lane 8 with lane 4). On the other hand, in the GLUT2 promoter sequence, the H153N mutant showed no inhibition of HNF-1/HNF-1ß heterodimer binding, but it did show increasing binding of the HNF-1/HNF-1ß heterodimer and HNF-1ß homodimer (Fig. 6B, compare lane 8 with lane 4). This increment might involve the H153N mutant, considering the increased binding of HNF-1ß in Fig. 3C. These results indicate that the H153N mutant also has a promoter-specific repressive effect on HNF-1/HNF-1ß heterodimer and that the repressive effect might be exerted through the inhibition of the DNA binding. |
Discussion |
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We found that the H153N mutant has diminished transcriptional activity and DNA binding activity. The H153N mutant had a promoter-specific dominant-negative effect on wild-type HNF-1ß and inhibited its DNA binding. Because the N-terminal dimerization domain was intact in the H153N mutant, it is suspected that the mutant can dimerize with wild-type HNF-1ß. It has been reported that HNF-1 forms a dimer before binding to DNA (26). We consider that the mutant inhibited wild-type HNF-1ß DNA binding by forming a dimer, which could not bind the insulin mini-enhancer element. On the other hand, in the GLUT2 promoter, the mutant/wild-type dimer seems to be able to bind DNA. However, this dimer might be transcriptionally silent on this promoter, considering that the mutant has no transcriptional effect on wild-type HNF-1ß.
We also found that the H153N mutant had a promoter-specific repressive effect on the heterodimer partner, HNF-1, probably by inhibiting its DNA binding. Considering that the HNF-1 dose used was not the maximum and that wild-type HNF-1ß had additional transcriptional activity on HNF-1, this repression may not be due to squelching. Promoter-specific repression by the H153N mutant was also observed for the transactivation and DNA binding of the HNF-1/HNF-1ß heterodimer. Considering our finding that the binding of HNF-1ß to the insulin mini-enhancer element was stronger than to the GLUT2 promoter, it is suggested that HNF-1ß binding is essential in the insulin mini-enhancer element. Thus, the HNF-1/HNF-1ß H153N heterodimer may not bind to the insulin mini-enhancer element but binds to the GLUT2 promoter, as with the HNF-1ß wild-type/H153N dimer. The binding preference for HNF-1 or HNF-1ß might be due to a minor sequence difference in the HNF-1 sites.
We also found a cell-specific regulation by HNF-1ß. We found that wild-type HNF-1ß showed HNF-1 repression in HeLa cells, in contrast to the activation in other cell lines, using the same insulin mini-enhancer element. In this cell line, the H153N mutant repressed HNF-1 most prominently. It is reported that HNF-1 recruits multiple coactivators, including dimerization cofactor of HNF-1, cAMP response element-binding protein, P300/cAMP response element binding protein-associated factor, steroid receptor coactivator-1, and receptor associated coactivator 3, to induce synergistic transcriptional activation (27, 28). Considering that HNF-1 is not expressed in HeLa cells, it was suggested that the difference among cell lines is due to differences in other factors that form a protein complex with HNF-1/HNF-1ß.
Taken together, our results indicate that H153N mutant has promoter- and tissue-specific basal transcriptional activity, a dominant-negative effect on HNF-1ß, and an HNF-1 repressive effect. The repressive effect on HNF-1 seems to be specific to H153N mutation because the repression was not apparent in other reported mutants (data not shown). The time-specific HNF-1ß expression profile and the differential regulation by HNF-1ß on HNF-1/1ß target promoters suggest that HNF-1ß has a regulatory role in HNF-1 target gene expression (8, 9, 10, 11). Moreover, it has recently been reported that HNF-1 and HNF-1ß controls the transcription of genes involved in bile acid transport and metabolism (17, 18). Thus, we consider that the specific features in the biliary systems in this patient might be caused by HNF-1ß insufficiency in conjunction with the repression of HNF-1 activity, especially in an HNF-1ß-dominant state. The spontaneous recovery of cholestasis might have been related to the change in the ratio of HNF-1 to HNF-1ß expression levels, i.e. changes in the HNF-1 dominant state. However, we cannot exclude the possibility that the biliary manifestation was only due to the HNF-1ß dominant-negative effect, considering the phenotype of HNF-1ß conditional knockout mice (17). It is difficult to infer because of the difference between homozygous mutant mice and heterozygous human. However, we think this is not the case because other patients with dominant-negative mutation do not have biliary manifestation. The neonatal history of the paternal family members was not obtained, and its cosegregation with hepatic dysfunction and the mutation remains unknown. We could not rule out the possibility that other genes contribute to the phenotypes.
Liver dysfunction, which might be more severe than in other reported pedigrees and might lead to liver cirrhosis and cancer in this pedigree, is also suspected to be due to HNF-1ß and HNF-1 repression, considering the fact that HNF-1 knockout mice have prominent liver dysfunction (29, 30). However, because DNA analysis of the paternal family could not be performed, the relationship remains unknown. Further accumulation of patients and molecular studies are necessary. It is also suspected that the intrauterine growth retardation of this patient might have been due to insufficient production of IGF-I caused by HNF-1 repression by the mutant HNF-1ß during his fetal period (31, 32). In these respects, the phenotype of patients who have both heterozygous HNF-1 and HNF-1ß mutations or the phenotype of its animal model (HNF-1+/-/HNF-1ß+/-) would be of interest.
In summary, we reported a novel missense mutation of the HNF-1ß gene in a patient with neonatal cholestasis and liver dysfunction in addition to the common features of MODY5. The mutant HNF-1ß had diminished transcriptional activity and DNA binding activity. This finding was quite common, with few exceptions, among other HNF-1ß mutants as reported in a very recent article (33). Furthermore, we found that the mutant had promoter- and cell-specific repressive effects on both wild-type HNF-1ß and HNF-1. Although the cosegregation of the mutation with the clinical manifestations remains to be clarified, we consider that the specific features of this patient might have been caused by the insufficiency of HNF-1ß activity in conjunction with the repression of HNF-1 activity in selected promoters and tissues.
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Acknowledgments |
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Footnotes |
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Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; GLUT2, glucose transporter-2; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young.
Received July 28, 2003.
Accepted December 8, 2003.
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References |
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gene in maturity-onset diabetes of the young (MODY3). Nature 384:455–458[CrossRef][Medline]
to HNF-1ß. J Biol Chem 276:32122–32128 and 1ß. J Biol Chem 273:28408–28418 is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet 27:375–382[CrossRef][Medline]
-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 338:653–661. Mol Cell 10:1129–1137[CrossRef][Medline]
function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic ß-cell line. EMBO J 17:6701–6713[CrossRef][Medline]
and HNF-1ß (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev 5:1042–1056 gene: elimination of liver dysfunction to establish a mouse MODY3 model. Mol Cell Biol 23:923–932 knockout mouse. Mol Cell Biol 18:3059–3068 activates promoter 1 of the human insulin-like growth factor I gene via two distinct binding sites. Mol Endocrinol 9:1488–1499[Abstract]
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