Canonical Wnt signaling is essential for a plethora of biological processes ranging from early embryogenesis to aging. Malfunctions of this crucial signaling pathway are associated with various developmental defects and diseases, including cancer. Although TCF/LEF transcription factors (TCF/LEFs) are known to be essential for this pathway, the regulation of their intracellular levels is not completely understood. Here, we show that the lysine demethylase KDM2A promotes the proteasomal destabilization of TCF/LEFs independently of its demethylase domain. We found that the KDM2A-mediated destabilization of TCF/LEFs is dependent on the KDM2A zinc finger CXXC domain. Furthermore, we identified the C-terminal region of TCF7L2 and the CXXC domain of KDM2A as the domains responsible for the interaction between the two proteins. Our study is also the first to show that endogenous TCF/LEF proteins undergo KDM2A-mediated proteasomal degradation in a neddylation-dependent manner. Here, we reveal a completely new mechanism that affects canonical Wnt signaling by regulating the levels of TCF/LEF transcription factors through their KDM2A-promoted proteasomal degradation.
- MeSH
- beta Catenin * metabolism MeSH
- Lysine * MeSH
- Wnt Signaling Pathway MeSH
- Zinc Fingers MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences. METHODS: This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs). RESULTS: The strongest T2DM markers (P < 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P < 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (>0.6) further improved (P < 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P < 0.0001), nephropathy (P < 0.005) and leg ischemia (P < 0.0005). CONCLUSIONS: If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.
- MeSH
- Genome-Wide Association Study MeSH
- Diabetes Mellitus, Type 2 * complications genetics MeSH
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics MeSH
- Genetic Predisposition to Disease MeSH
- Polymorphism, Single Nucleotide MeSH
- Diabetes Complications * MeSH
- Humans MeSH
- Risk Factors MeSH
- T Cell Transcription Factor 1 genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Úvod: Ischemická choroba srdeční (ICHS) a ischemická choroba dolních končetin (ICHDK) jsou časté komplikace u pacientů s diabetem druhého typu (T2DM). Jejich včasná předpověď analýzou genetické predisposice by byla klinicky velmi významná. Porovnávali jsme polygenní skóre a výskyt ICHDK a ICHS u českých pacientů s T2DM. Metodika: Z 21 variant, analyzovaných u celkem 1 032 pacientů s T2DM (359 žen a 673 mužů) bylo vybráno 7 (v genech pro FTO, TCF7L2, IRS1, JAZF, ZMIZ, WFS1 a NOTCH2) pro stanovení neváženého polygenního skóre. Protektivní genotyp měl hodnotu 0, genotypy s alespoň jednou rizikovou alelou hodnotu 1. ICHS byla diagnostikována u 35,0 %, ICHDK u 17,5 % pacientů. Výsledky: Pozorovali jsme významný lineární trend výskytu ICHDK (P = 0,0002), ale ne ICHS (P = 0,25) v souvislosti s narůstajícím počtem rizikových alel – polygenní skóre P (pro trend) 0–2 3 4 5 6–7: ICHDK 4,6 % 14,7 % 16,0 % 21,0 % 23,5 %; P = 0,0002 vs ICHS 34,9 % 31,0 % 32,2 % 36,3 % 33,8 %; P = 0,25 ). Jedinci s polygenním skóre 6 a více mají oproti jedincům s hodnotami 0–2 OR (95% CI) pro výskyt ICHDK – 6,3 (1,9–21,3). Závěr: Polygenní skóre může být využito jako nástroj pro detekci jedinců se zvýšeným rizikem ICHDK, ale ne ICHS.
- Publication type
- Meeting Abstract MeSH
The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.
- MeSH
- beta Catenin genetics metabolism MeSH
- Candida albicans MeSH
- Granulocytes metabolism MeSH
- Candidiasis genetics metabolism MeSH
- Myelopoiesis * MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Transcription Factor 7-Like 2 Protein metabolism MeSH
- Receptors, Colony-Stimulating Factor biosynthesis genetics MeSH
- Signal Transduction * MeSH
- TCF Transcription Factors genetics metabolism MeSH
- Up-Regulation * MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: The Czech governmental study suggests up to a 25% higher prevalence of type 2 diabetes mellitus (T2DM) in the Roma population than within the majority population. It is not known whether and to what extent these differences have a genetic background. METHODS: To analyze whether the frequencies of the alleles/genotypes of the FTO, TCF7L2, CDKN2A/2B, MAEA, TLE4, IGF2BP2, ARAP1, and KCNJ11 genes differ between the two major ethnic groups in the Czech Republic, we examined them in DNA samples from 302 Roma individuals and 298 Czech individuals. RESULTS: Compared to the majority population, Roma are more likely to carry risk alleles in the FTO (26% vs. 16% GG homozygotes, p < .01), IGF2BP2 (22% vs. 10% TT homozygotes, p < .0001), ARAP1 (98% vs. 95% of A allele carriers, p < .005), and CDKN2A/2B (81% vs. 66% of TT homozygotes, p < .001) genes; however, less frequently they are carriers of the TCF7L2 risk allele (34% vs. 48% of the T allele p < .0005). Finally, we found significant accumulation of T2DM-associated alleles between the Roma population in comparison with the majority population (25.4% vs. 15.2% of the carriers of at least 12 risk alleles; p < .0001). CONCLUSION: The increased prevalence of T2DM in the Roma population may have a background in different frequencies of the risk alleles of genes associated with T2DM development.
- MeSH
- Adiposity MeSH
- Cholesterol blood MeSH
- Diabetes Mellitus, Type 2 blood ethnology genetics MeSH
- Adult MeSH
- Gene Frequency * MeSH
- Genetic Loci * MeSH
- Blood Glucose analysis MeSH
- Middle Aged MeSH
- Humans MeSH
- Polymorphism, Genetic MeSH
- Roma genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
- Publication type
- Meeting Abstract MeSH
Generation of neurons in the embryonic neocortex is a balanced process of proliferation and differentiation of neuronal progenitor cells. Canonical Wnt signalling is crucial for expansion of radial glial cells in the ventricular zone and for differentiation of intermediate progenitors in the subventricular zone. We detected abundant expression of two transcrtiption factors mediating canonical Wnt signalling, Tcf7L1 and Tcf7L2, in the ventricular zone of the embryonic neocortex. Conditional knock-out analysis showed that Tcf7L2, but not Tcf7L1, is the principal Wnt mediator important for maintenance of progenitor cell identity in the ventricular zone. In the absence of Tcf7L2, the Wnt activity is reduced, ventricular zone markers Pax6 and Sox2 are downregulated and the neuroepithelial structure is severed due to the loss of apical adherens junctions. This results in decreased proliferation of radial glial cells, the reduced number of intermediate progenitors in the subventricular zone and hypoplastic forebrain. Our data show that canonical Wnt signalling, which is essential for determining the neuroepithelial character of the neocortical ventricular zone, is mediated by Tcf7L2.
- MeSH
- Cell Differentiation genetics MeSH
- Chloride-Bicarbonate Antiporters MeSH
- Down-Regulation genetics MeSH
- Embryo, Mammalian MeSH
- Hippocampus cytology embryology MeSH
- Mutation genetics MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Neocortex cytology embryology MeSH
- Neural Stem Cells physiology MeSH
- Neurogenesis physiology MeSH
- Neuroglia MeSH
- Neurons physiology MeSH
- Cell Count MeSH
- Cell Proliferation genetics MeSH
- Transcription Factor 7-Like 2 Protein genetics metabolism MeSH
- T-Box Domain Proteins metabolism MeSH
- Wnt Proteins metabolism MeSH
- Retinal Ganglion Cells physiology MeSH
- Signal Transduction genetics MeSH
- SOXB1 Transcription Factors metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as TCF1, LEF1, TCF3, and TCF4, respectively). The proteins display common structural features and are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed in gene targeting studies; however, individual family members also exhibit unique features that are not recapitulated by the related proteins. In the present viewpoint, we summarized our current knowledge about the specific features of individual TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, and phenotypes obtained upon gene targeting in the mouse. In addition, we employed several publicly available databases and web tools to evaluate the expression patterns and production of gene-specific isoforms of the TCF/LEF family members in human cells and tissues.
- Publication type
- Journal Article MeSH
- Review MeSH
Farmakogenetika je vedný odbor, ktorý skúma efekt jednotlivých liekov v závislosti od genotypu. V súčasnosti sú liečebné odporúčania pre liečbu niektorých monogenénových diabetov založené na genetickej diagnostike. Aj v oblasti farmakogenetiky perorálnych antidiabetík boli už publikované prvé štúdie, ktoré zistili asociácie jednotlivých génových variantov s liečebnou odozvou. Odozva na deriváty sulfonylurey bola signifikantne asociovaná s variantmi KCNJ11/ABCC8, TCF7L2 a CYP2C9. Odozva na liečbu metformínom bola asociovaná s variantmi génov ATM a SLC47A1. Odozva na liečbu glitazónmi bola asociovaná s variantom génu PPARG. Terapeutická odozva na liečbu gliptínmi bola asociovaná s variantmi génov TCF7L2 a CTRB1/2. Je možné očakávať, že v blízkej budúcnosti budú farmakogenetické poznatky využívané aj pri personalizácii liečby diabetu 2. typu.
Pharmacogenetics is the study of how genes (individual genotypes) affect a person‘s response to drugs. At present, recommendations made about the treatment of some monogenic forms of diabetes are based on genetic diagnostics. The first studies in the field of pharmacogenetics of oral antidiabetics have now been published which have identified associations of individual genetic variants with response to treatment. The response to sulfonylurea derivatives was significantly associated with the variants KCNJ11/ABCC8, TCF7L2 and CYP2C9. The response to metformin treatment was associated with the genetic variants ATM and SLC47A1. The response to treatment with glitazones was associated with the genetic variant PPARG. The therapeutic response to the treatment with gliptins was associated with the genetic variants TCF7L2 and CTRB1/2. It may be expected that in the near future pharmacogenetic knowledge will also be used within personalized treatment of type 2 diabetes.
- MeSH
- Diabetes Mellitus, Type 2 drug therapy genetics MeSH
- Diabetes Mellitus * drug therapy genetics MeSH
- Pharmacogenetics * MeSH
- Genotype MeSH
- Hypoglycemic Agents pharmacology MeSH
- Dipeptidyl-Peptidase IV Inhibitors pharmacology MeSH
- Humans MeSH
- Metformin MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Keywords
- mozková inzulinová rezistence,
- MeSH
- Early Diagnosis MeSH
- Dementia * diagnosis etiology MeSH
- Diabetes Mellitus, Type 2 * diagnosis etiology drug therapy classification prevention & control MeSH
- Body Fat Distribution MeSH
- Phenotype * MeSH
- Glycated Hemoglobin * analysis standards MeSH
- Hypoglycemic Agents administration & dosage pharmacology therapeutic use MeSH
- Insulin Resistance * MeSH
- Liver MeSH
- Clinical Trials as Topic MeSH
- Congresses as Topic * MeSH
- Humans MeSH
- Metabolic Syndrome MeSH
- Multicenter Studies as Topic MeSH
- Obesity MeSH
- Prediabetic State * MeSH
- Primary Prevention MeSH
- Transcription Factor 7-Like 2 Protein * diagnostic use physiology MeSH
- Risk MeSH
- Risk Factors MeSH
- Statistics as Topic MeSH
- Treatment Outcome MeSH
- Life Style MeSH
- Check Tag
- Humans MeSH
