Genomes and Genes
tcf transcription factors
Summary: A family of DNA-binding proteins that are primarily expressed in T-LYMPHOCYTES. They interact with BETA CATENIN and serve as transcriptional activators and repressors in a variety of developmental processes.
- Shu L, Matveyenko A, Kerr Conte J, Cho J, McIntosh C, Maedler K. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet. 2009;18:2388-99 pubmed publisher..Our findings suggest that beta-cell function and survival are regulated through an interplay between TCF7L2 and GLP-1R/GIP-R expression and signaling in T2DM. ..
- MacDonald B, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9-26 pubmed publisher..Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications. ..
- Pomerantz M, Ahmadiyeh N, Jia L, Herman P, Verzi M, Doddapaneni H, et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet. 2009;41:882-4 pubmed publisher..These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant. ..
- Pilgaard K, Jensen C, Schou J, Lyssenko V, Wegner L, Brøns C, et al. The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia. 2009;52:1298-307 pubmed publisher..Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2. ..
- Biechele T, Moon R. Assaying beta-catenin/TCF transcription with beta-catenin/TCF transcription-based reporter constructs. Methods Mol Biol. 2008;468:99-110 pubmed publisher..Its enhanced sensitivity, increased dynamic range, and lentiviral platform provide a reporter system that will keep pace with the needs of scientists in the field. ..
- Marquezine G, Pereira A, Sousa A, Mill J, Hueb W, Krieger J. TCF7L2 variant genotypes and type 2 diabetes risk in Brazil: significant association, but not a significant tool for risk stratification in the general population. BMC Med Genet. 2008;9:106 pubmed publisher..Finally, confirming the biological association of a genetic marker does not guarantee improvement on already established screening tools based solely on demographic variables. ..
- Yang Q, Kardava L, St Leger A, Martincic K, Varnum Finney B, Bernstein I, et al. E47 controls the developmental integrity and cell cycle quiescence of multipotential hematopoietic progenitors. J Immunol. 2008;181:5885-94 pubmed..Thus, E47 appears to regulate the developmental and functional integrity of early hematopoietic subsets in part through effects on p21-mediated cell cycle quiescence. ..
- Ye S, Tan L, Yang R, Fang B, Qu S, Schulze E, et al. Pleiotropy of glycogen synthase kinase-3 inhibition by CHIR99021 promotes self-renewal of embryonic stem cells from refractory mouse strains. PLoS ONE. 2012;7:e35892 pubmed publisher..These findings would be useful to improve the availability of normally non-permissive mouse strains as research tools. ..
- Pulizzi N, Lyssenko V, Jonsson A, Osmond C, Laakso M, Kajantie E, et al. Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes. Diabetologia. 2009;52:825-9 pubmed publisher..Low birthweight might affect the strength of the association of some common variants (HHEX, CDKN2A/2B and JAZF1) with type 2 diabetes. These findings need to be replicated in independent cohorts. ..
- Prokunina Olsson L, Welch C, Hansson O, Adhikari N, Scott L, Usher N, et al. Tissue-specific alternative splicing of TCF7L2. Hum Mol Genet. 2009;18:3795-804 pubmed publisher..Alternative splicing of TCF7L2 in pancreatic islets warrants future studies. GenBank Accession Numbers: FJ010164-FJ010174. ..
- Sanghera D, Ortega L, Han S, Singh J, Ralhan S, Wander G, et al. Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk. BMC Med Genet. 2008;9:59 pubmed publisher..Further investigations are warranted to understand the pathway-based functional implications of these important loci in T2D pathophysiology in different ethnicities. ..
- Gaulton K, Nammo T, Pasquali L, Simon J, Giresi P, Fogarty M, et al. A map of open chromatin in human pancreatic islets. Nat Genet. 2010;42:255-9 pubmed publisher..These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility. ..
- Sokol S. Maintaining embryonic stem cell pluripotency with Wnt signaling. Development. 2011;138:4341-50 pubmed publisher..Although the results of recent studies of the Wnt/?-catenin pathway in ES cells appear to be surprising and controversial, they converge on the same conserved mechanism that leads to the inactivation of TCF3-mediated repression. ..
- Locke J, da Silva Xavier G, Rutter G, Harries L. An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor (TCF/LEF)-dependent target genes. Diabetologia. 2011;54:3078-82 pubmed publisher..These findings may provide new insights into the association of TCF7L2 with susceptibility to type 2 diabetes. ..
- Prokunina Olsson L, Kaplan L, Schadt E, Collins F. Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes. PLoS ONE. 2009;4:e7231 pubmed publisher..Expression of TCF7L2 alternatively spliced forms may have different functional roles in omental and subcutaneous adipose tissue but is not associated with SNPs rs7903146 and rs12255372 or T2D status. ..
- Palka Hamblin H, Gierut J, Bie W, Brauer P, Zheng Y, Asara J, et al. Identification of beta-catenin as a target of the intracellular tyrosine kinase PTK6. J Cell Sci. 2010;123:236-45 pubmed publisher..The ability of PTK6 to negatively regulate beta-catenin/TCF transcription by modulating levels of TCF4 and TLE/Groucho could contribute to its growth-inhibitory activities in vivo. ..
- Zhou T, Zhou K, Lee K, Gao G, Lyons T, Kowluru R, et al. The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy. Diabetologia. 2011;54:459-68 pubmed publisher..Lipid peroxidation products activate the canonical WNT pathway through oxidative stress, which plays an important role in the development of retinal diseases. ..
- Tuupanen S, Turunen M, Lehtonen R, Hallikas O, Vanharanta S, Kivioja T, et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat Genet. 2009;41:885-90 pubmed publisher..Our work provides evidence that the common CRC predisposition associated with 8q24 arises from enhanced responsiveness to Wnt signaling. ..
- Luo Y, Wang H, Han X, Ren Q, Wang F, Zhang X, et al. Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in East Asian population. Diabetes Res Clin Pract. 2009;85:139-46 pubmed publisher..SNPs in TCF7L2 were strongly associated with the risk of T2DM in East Asian population. But the contribution of its genetic variants to the epidemic of type 2 diabetes in East Asian was relatively low. ..
- Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L. A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer. Proc Natl Acad Sci U S A. 2008;105:9697-702 pubmed publisher..Taken together, the results from our screen and studies focused on members of the TCF/LEF gene family refine our understanding of how aberrant Wnt pathway activation sustains CRC growth. ..
- Doghman M, Cazareth J, Lalli E. The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab. 2008;93:3222-5 pubmed publisher..Inhibitors of the Tcf/beta-catenin complex may prove useful in the treatment of adrenocortical tumors in which multiple genetic alterations have accumulated. ..
- Reinehr T, Friedel S, Mueller T, Toschke A, Hebebrand J, Hinney A. Evidence for an influence of TCF7L2 polymorphism rs7903146 on insulin resistance and sensitivity indices in overweight children and adolescents during a lifestyle intervention. Int J Obes (Lond). 2008;32:1521-4 pubmed publisher..This finding further suggests that this polymorphism might be involved in glucose metabolism. ..
- Wegner L, Hussain M, Pilgaard K, Hansen T, Pedersen O, Vaag A, et al. Impact of TCF7L2 rs7903146 on insulin secretion and action in young and elderly Danish twins. J Clin Endocrinol Metab. 2008;93:4013-9 pubmed publisher..This suggests that the primary defect of rs7903146 T-allele carriers is impairment of insulin secretion rather than a defect in insulin action in peripheral tissues. ..
- Saegusa M, Hashimura M, Kuwata T, Hamano M, Watanabe J, Kawaguchi M, et al. Transcription factor Egr1 acts as an upstream regulator of beta-catenin signalling through up-regulation of TCF4 and p300 expression during trans-differentiation of endometrial carcinoma cells. J Pathol. 2008;216:521-32 pubmed publisher
- Yochum G, Cleland R, Goodman R. A genome-wide screen for beta-catenin binding sites identifies a downstream enhancer element that controls c-Myc gene expression. Mol Cell Biol. 2008;28:7368-79 pubmed publisher..Our findings indicate that a downstream enhancer element provides the principal regulation of c-Myc expression. ..
- Beck K, Peak M, Ota T, Nemazee D, Murre C. Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J Exp Med. 2009;206:2271-84 pubmed publisher..We propose that in the pre-B and immature B cell compartments, gradients of E12 and E47 activities are established to mechanistically regulate the sequential rearrangement of the Ig light chain genes. ..
- Kelly K, Ng D, Jayakumaran G, Wood G, Koide H, Doble B. ?-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell. 2011;8:214-27 pubmed publisher..Collectively, our data suggest previously underappreciated, divergent TCF-dependent and TCF-independent roles for ?-catenin in ESCs. ..
- Kim Y, Ma H, Oehler V, Gang E, Nguyen C, Masiello D, et al. The gamma catenin/CBP complex maintains survivin transcription in ?-catenin deficient/depleted cancer cells. Curr Cancer Drug Targets. 2011;11:213-25 pubmed..Therefore, we believe that the ability of ICG-001 to block both the CBP/?-catenin interaction and the CBP/?-catenin interaction may have clinical significance in cancers in which ?-catenin plays a significant transcriptional role. ..
- Kovacs P, Berndt J, Ruschke K, Kloting N, Schön M, Körner A, et al. TCF7L2 gene expression in human visceral and subcutaneous adipose tissue is differentially regulated but not associated with type 2 diabetes mellitus. Metabolism. 2008;57:1227-31 pubmed publisher..Based on our data, TCF7L2 mRNA expression is fat-depot specific but does not seem to provide the mechanistic link explaining genetic association with T2DM. ..
- Weise A, Bruser K, Elfert S, Wallmen B, Wittel Y, Wöhrle S, et al. Alternative splicing of Tcf7l2 transcripts generates protein variants with differential promoter-binding and transcriptional activation properties at Wnt/beta-catenin targets. Nucleic Acids Res. 2010;38:1964-81 pubmed publisher..Still, the cell-type-specific complement of TCF4 isoforms is likely to be a major determinant for the context-dependent transcriptional output of Wnt/beta-catenin signalling. ..
- Lim K, Han C, Dai Y, Shen M, Wu T. Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking beta-catenin and cyclooxygenase-2. Mol Cancer Ther. 2009;8:3046-55 pubmed publisher..These findings provide important preclinical evidence and molecular insight for utilization of omega-3 PUFAs for the chemoprevention and treatment of human HCC. ..
- Robertson B, Chellaiah M. Osteopontin induces beta-catenin signaling through activation of Akt in prostate cancer cells. Exp Cell Res. 2010;316:1-11 pubmed publisher..This work describes an important aspect of cancer progression induced by OPN. ..
- van Hoek M, Dehghan A, Witteman J, van Duijn C, Uitterlinden A, Oostra B, et al. Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study. Diabetes. 2008;57:3122-8 pubmed publisher..Combining genetic variants has low predictive value for future type 2 diabetes at a population-based level. The genetic polymorphisms only marginally improved the prediction of type 2 diabetes beyond clinical characteristics. ..
- Alsmadi O, Al Rubeaan K, Mohamed G, Alkayal F, Al Saud H, Al Saud N, et al. Weak or no association of TCF7L2 variants with Type 2 diabetes risk in an Arab population. BMC Med Genet. 2008;9:72 pubmed publisher..Future studies in this population are required to confirm our findings and may indicate the presence of yet to be defined genetic risk factors for T2D. ..
- Jin T, George Fantus I, Sun J. Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell Signal. 2008;20:1697-704 pubmed publisher..These observations provide new insight to understand how Wnt, insulin/growth factors, and FOXOs are involved in versatile physiological events and the development and progression of various human diseases. ..
- Musso G, Gambino R, Pacini G, Pagano G, Durazzo M, Cassader M. Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH. Hepatology. 2009;49:426-35 pubmed publisher..Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients. ..
- Liu P, Chang Y, Jiang Y, Chen W, Chang T, Kuo S, et al. Genetic variants of TCF7L2 are associated with insulin resistance and related metabolic phenotypes in Taiwanese adolescents and Caucasian young adults. J Clin Endocrinol Metab. 2009;94:3575-82 pubmed publisher..These findings support an important role for T2D risk-conferring gene TCF7L2 in insulin resistance in both Taiwanese and Caucasian youth and underscore the emerging role of Wnt signaling in insulin resistance. ..
- Da Silva Xavier G, Loder M, McDonald A, Tarasov A, Carzaniga R, Kronenberger K, et al. TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes. 2009;58:894-905 pubmed publisher..TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles. ..
- Klingel S, Morath I, Strietz J, Menzel K, Holstein T, Gradl D. Subfunctionalization and neofunctionalization of vertebrate Lef/Tcf transcription factors. Dev Biol. 2012;368:44-53 pubmed publisher..We propose that the vertebrate specific diversification of Tcfs in vertebrates resulted in subfunctionalization of a Tcf that already united most of the Lef/Tcf functions...
- Osmark P, Hansson O, Jonsson A, Rönn T, Groop L, Renstrom E. Unique splicing pattern of the TCF7L2 gene in human pancreatic islets. Diabetologia. 2009;52:850-4 pubmed publisher..Further experiments will be needed to determine the direction of this correlation, and larger cohorts needed to unequivocally resolve whether there is a relationship between genotype and splicing in islets. ..
- Pascoe L, Frayling T, Weedon M, Mari A, Tura A, Ferrannini E, et al. Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles. Diabetologia. 2008;51:1989-92 pubmed publisher..001 and p = 0.003, respectively). This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals. ..
- Koslowski M, Kübler I, Chamaillard M, Schaeffeler E, Reinisch W, Wang G, et al. Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. PLoS ONE. 2009;4:e4496 pubmed publisher..38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis...
- Chang M, Chang J, Gangopadhyay A, Shearer A, Cadigan K. Activation of wingless targets requires bipartite recognition of DNA by TCF. Curr Biol. 2008;18:1877-81 pubmed publisher..Our data suggest that DNA recognition by fly TCF occurs through a bipartite mechanism, involving both the HMG domain and the C-clamp, which enables TCF to locate and activate WREs in the nucleus. ..
- Hu M, Kurobe M, Jeong Y, Fuerer C, Ghole S, Nusse R, et al. Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology. 2007;133:1579-91 pubmed..These findings may lend insight to the consequences of increased canonical Wnt signaling during periods of chronic liver injury. ..
- Liu Z, Habener J. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008;283:8723-35 pubmed publisher..Wnt signaling appears to mediate GLP-1-induced beta cell proliferation raising possibilities for novel treatments of diabetes. ..
- Yoshikawa H, Matsubara K, Zhou X, Okamura S, Kubo T, Murase Y, et al. WNT10B functional dualism: beta-catenin/Tcf-dependent growth promotion or independent suppression with deregulated expression in cancer. Mol Biol Cell. 2007;18:4292-303 pubmed..We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator. ..
- Weedon M. The importance of TCF7L2. Diabet Med. 2007;24:1062-6 pubmed..This short review focuses on the TCF7L2 finding and discusses its significance for Type 2 diabetes genetic studies and for clinical practice. ..