Disease relevance of TCF7L2

• METHODS: We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer (BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals [1].
• We conclude that the TCF7L2 T at-risk allele variation (rs7903146) predicts hyperglycemia incidence in a general French population, possibly through a deleterious effect on insulin secretion [2].
• Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population [3].
• Additionally, we find that hypoxia inducible factor-1alpha (HIF-1alpha) competes with TCF-4 for direct binding to beta-catenin [4].
• Mutations in the Wnt components AXIN1, AXIN2 and TCF4 have been found in microsatellite-unstable colon cancers, but it is not clear in every case whether these changes are functional [5].

High impact information on TCF7L2

• The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis [6].
• A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)) [6].
• Crystal Structure of a beta-Catenin/BCL9/Tcf4 Complex [7].
• However, it is still uncertain whether beta-catenin exerts its oncogenic function solely by coactivating the target genes of T-cell factor-4 (TCF4) [8].
• Here we report the crystal structure of a beta-catenin-Tcf4 complex at 2.0 A resolution [9].

Biological context of TCF7L2

• Assignment of the TCF-4 gene (TCF7L2) to human chromosome band 10q25.3 [10].
• Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes [1].
• Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk [1].
• These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D [11].
• Our results indicate that both Sfrp1 and TCF-4 repress Wnt signaling in breast tissue and their downregulation contributes to the activation of Wnt signaling [12].

Anatomical context of TCF7L2

• TCF7L2 is expressed in most human tissues, including mature pancreatic beta-cells, with the exception of the skeletal muscle [13].
• Transcription Factor TCF7L2 Genetic Study in the French Population: Expression in Human {beta}-Cells and Adipose Tissue and Strong Association With Type 2 Diabetes [13].
• Interfering with either Sfrp1 or TCF-4 in this cell line enhanced CD24 expression [12].
• BMPs restrict the position of premuscle masses in the limb buds by influencing Tcf4 expression [14].
• Human immunodeficiency virus type 1 Tat prevents dephosphorylation of Sp1 by TCF-4 in astrocytes [15].

Associations of TCF7L2 with chemical compounds

• Haplotypes of Transcription Factor 7-Like 2 (TCF7L2) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans [16].

Other interactions of TCF7L2

• CONCLUSION: The TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population [17].
• METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies [18].
• We previously observed a modest logarithm of odds score of 0.61 on chromosome 10q, approximately 1 Mb from TCF7L2, in the Finland-United States Investigation of NIDDM Genetics study [19].

Analytical, diagnostic and therapeutic context of TCF7L2

• Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study [1].
• TCF7L2 Variation Predicts Hyperglycemia Incidence in a French General Population: The Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) Study [2].
• Co-immunoprecipitation in HEK-293T cells and yeast two-hybrid screen in Y190 cells were performed to identify the interaction between Tcf4 with Daxx and to map the binding regions of Tcf4 [20].
• Results from a GST pull-down assay, as well as combined immunoprecipitation and Western blot analysis of protein extracts from U-87 MG cells, revealed an interaction of Sp1 with TCF-4 [15].

References