Disease relevance of TCF1

• Bi-allelic inactivation of TCF1 in hepatic adenomas [1].
• G4 was a heterogeneous subgroup of tumors including TCF1-mutated hepatocellular adenomas and carcinomas [2].
• Identification of seven novel nucleotide variants in the hepatocyte nuclear factor-1alpha (TCF1) promoter region in MODY patients [3].
• Since approximately 20% of Caucasian patients with HNF-1alpha mutations have been shown to be obese or overweight, we also examined the association of genetic variations in TCF1 with body weight in Japanese subjects [4].
• The aim of this study was to determine the prevalence of mutations in the hepatocyte nuclear factor (HNF)-1alpha gene (TCF1) in a large group of Japanese patients with early-onset non-Type I (insulin-dependent) diabetes mellitus [4].

High impact information on TCF1

• Heterozygous germline mutations of TCF1 have been identified in individuals affected with maturity-onset diabetes of the young type 3 (MODY3; ref. 3). Bi-allelic inactivation of TCF1 was found in 10 of 16 screened adenomas, and heterozygous germline mutation were present in three affected individuals [1].
• A minimal common region of deletion was defined in 12q24 that included the gene TCF1 (transcription factor 1), encoding hepatocyte nuclear factor 1 (HNF1; refs 1,2) [1].
• The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans [5].
• Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years) [6].
• Transcription factor p91 contains a SH2 domain and is activated by tyrosine phosphorylation [7].

Chemical compound and disease context of TCF1

• Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications [8].
• The reverse tetracycline-dependent transactivator system was employed in insulinoma INS-1 cells to achieve controlled inducible expression of hepatocyte nuclear factor-1 alpha (HNF1 alpha)-P291fsinsC, the most common mutation associated with subtype 3 of maturity-onset diabetes of the young (MODY3) [9].
• In support of this idea, expression of vHNF1 but not HNF1 is induced upon treatment of the embryonal carcinoma cell line F9 with retinoic acid [10].
• HNF1 alpha expression in cultured hepatoma cells was decreased approximately 50% after 12 hours' exposure to 100 micromol/L chenodeoxycholic acid (CDCA) [11].
• Mutations in these liver-enriched transcription factors result in two forms of early-onset type 2 diabetes (maturity-onset diabetes of the young [MODY]), MODY3 and MODY1, which are characterized by impaired glucose-stimulated insulin secretion, early disease onset, and autosomal dominant inheritance [12].

Biological context of TCF1

• METHODS: At first, a series of 10 adenomas and 29 colon cancers regardless of microsatellite instability status were screened for TCF1 mutations on the entire coding sequence [13].
• Ten exons and flanking introns of TCF1 of these patients were directly sequenced for mutations [4].
• The TCF1 gene was found to be located on chromosome 12 in both man and rat, thereby defining a new segment of homology between these two species (and a segment of mouse chromosome 5) [14].
• The phenotype and clinical profile of some of the studied patients is compatible with that of patients carrying mutations in the TCF1 or TCF14 genes, while others may carry mutations in different loci [15].
• The results also showed that sFRP3 treatment attenuates some of the observed Wnt 3a effects on MSCs, and that inhibition of canonical Wnt signaling using a dominant negative TCF1 enhances MSC osteogenesis [16].

Anatomical context of TCF1

• Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1) [17].
• The mechanisms by which mutations in the HNF-1alpha gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function [18].
• The human T cell transcription factor-1 gene. Structure, localization, and promoter characterization [19].
• PUFA repress the promoter activity only in HNF4 alpha-cotransfected HeLa cells, whereas they have no effects on the promoter activity in HNF1 alpha-cotransfected HeLa cells [20].
• We identified hepatic nuclear factor 1 (HNF1) as an important liver-specific trans-acting element for the human ACAT2 gene using the human hepatocellular carcinoma cell lines HuH7 and HepG2 [21].

Associations of TCF1 with chemical compounds

• In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population [22].
• CONCLUSION/INTERPRETATION: These results suggest that the mutation of HNF-1alpha at codon 263 from arginine to leucine leads to the development of MODY3 through decreased insulin production and defective glucose sensing [23].
• The three subjects with HNF-1 beta diabetes also had abnormally high serum creatinine, uric acid, and blood urea nitrogen levels, which are consistent with impaired kidney function, and one of seven subjects with HNF-1 alpha diabetes had a mild elevation in creatinine and blood urea nitrogen levels [24].
• Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations [25].
• Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level [26].

Physical interactions of TCF1

• A HNF-1 binding site was identified in the NNMT basal promoter region [27].
• The bifunctional DCOH protein binds to HNF1 independently of its 4-alpha-carbinolamine dehydratase activity [28].
• Tcf1 in complex with beta-catenin is able to activate beta-catenin-dependent gene expression [29].
• Transcription factor binding experiments demonstrated that Salmonella or Sendai virus infection increased the binding of classical p50+p65 and alternative p52+RelB NF-kappaB proteins to both of the CCL19 promoter NF-kappaB elements [30].
• A mutation of the HNF4-binding site in the HNF1 gene promoter has also been associated with MODY [31].

Regulatory relationships of TCF1

• Characterization of the human HNF1 alpha gene promoter identified a consensus bile acid response element that binds and is activated by HNF4 alpha [11].
• Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene [32].
• These data provide evidence for an important stimulatory role of HNF1 in promoting UGT1A7 gene expression in rat liver [33].
• TCF-1 is specifically expressed in T-cell lineages and its interaction with beta-catenin is thought to be critical for early T-cell development [34].
• Transcription factor IRF-3 is post-translationally activated by Toll-like receptor (TLR) signaling and has critical roles in the regulation of innate immunity [35].

Other interactions of TCF1

• Functional studies of R137-K161del HNF-1beta revealed that it could not bind an HNF-1 target sequence or stimulate transcription of a reporter gene indicating that this is a loss-of-function mutation [36].
• The relative proportions classified as diabetic depended on whether fasting (38 % vs 22 %, glucokinase vs HNF-1 alpha) or 2-h values (19 % vs 44 %) were used [37].
• Control of ACAT2 liver expression by HNF1 [21].
• Differential activation of intestinal gene promoters: functional interactions between GATA-5 and HNF-1 alpha [38].
• This study demonstrates for the first time DCoH/HNF-1 alpha expression and transcriptional activity in human epidermal melanocytes in vitro and in situ and identified tyrosinase, the key enzyme for pigmentation, as a new transcriptional target [39].

Analytical, diagnostic and therapeutic context of TCF1

• Glucokinase subjects had a higher FPG than HNF-1 alpha subjects ([means +/- SD] 6.8 +/- 0.8 vs 6.0 +/- 1.9 mmol/l, p < 0.0001), a lower 2-h value (8.9 +/- 2.3 vs 11.2 +/- 5.2 mmol/l, p < 0.0001) and a lower OGTT increment (2-h - fasting) (2.1 +/- 2.3 vs 5.2 +/- 3.9 mmol/l, p < 0.0001) [37].
• By gel retardation assays with synthetic oligonucleotides, at least two distinct liver nuclear factors were identified, HNF-1 and HNF-2 (hepatocyte nuclear factors), which bound specifically to the first and second region, respectively [40].
• Administration of glucose by intravenous infusion for 42 h resulted in a significant increase in the amount of insulin secreted over the 5-9 mmol/l glucose concentration range in the control subjects and nondiabetic MODY3 subjects (by 38 and 35%, respectively), but no significant change was observed in the diabetic MODY3 subjects [41].
• METHODS: To assess the consequence of potential HNF-1 alpha splice site mutations we developed a nested reverse transcriptase PCR (RT-PCR) assay for the amplification of illegitimate HNF-1 alpha transcripts in Epstein Barr virus transformed lymphoblastoid cell lines [42].
• On Western blots of colorectal cancer cells, the TCF-1-specific monoclonal antibody 7H3 detected a similar heterogeneous spectrum of TCF-1 specific polypeptide chains [43].

References