Disease relevance of TCF3

• Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors in which beta-catenin/TCF3 mediated Wnt signaling is activated [1].
• Mapping of the 19p13 breakpoint in an ovarian carcinoma between the INSR and TCF3 loci [2].
• Co-immunoprecipitation analysis revealed the presence of endogenous TAL1/E2A complexes in Jurkat cells, a leukemic line derived from a T-ALL patient [3].
• In pro-B cell acute lymphoblastic leukemia (ALL), expression of the E2A-HLF fusion gene as a result of t(17;19)(q22;p13) is associated with poor prognosis, hypercalcemia, and hemorrhagic complications [4].
• The gene E2A on chromosome 19 is involved in recurrent chromosomal rearrangements associated with pediatric acute lymphoblastic leukemia [5].
• We propose that E2A proteins prevent lymphoma cell expansion, at least in part through regulation of Gfi1b and modulation of Gata3 expression [6].

Psychiatry related information on TCF3

• A potential role for Id and TAL1/E2A bHLH genes in hematopoiesis has been suggested by studies on immortalized cell lines [7].

High impact information on TCF3

• The generation of the earliest B cell progenitors depends on E2A and EBF, which coordinately activate the B cell gene expression program and immunoglobulin heavy-chain gene rearrangements at the onset of B-lymphopoiesis [8].
• Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX [9].
• The Tcf3-CBD forms an elongated structure with three binding modules that runs antiparallel to beta-catenin along the positively charged groove formed by the armadillo repeats [10].
• These results suggest a novel mechanism for regulating the dimerization status and DNA binding properties of E2A HLH transcription factors [11].
• When the disulfide bond is reduced by an activity present in muscle cell lysates or disrupted by site-directed mutagenesis, the monomeric form of the protein is strongly favored at 37 degrees C. These E2A monomers cannot bind DNA but heterodimerize efficiently with Id and MyoD [11].

Chemical compound and disease context of TCF3

• Lymphoid-specific expression of the Id3 gene in hematopoietic cells. Selective antagonism of E2A basic helix-loop-helix protein associated with Id3-induced differentiation of erythroleukemia cells [12].
• These results indicate the important role of the E2A gene products in the progression of CsA-induced EMT and provide novel insights into CsA-induced renal fibrosis [13].
• We have also demonstrated that an E2A-HLF chimera, derived from a t(17;19) translocation in pre-B acute lymphoblastic leukemia (ALL) cells, is capable of mediating expression from the Factor VIII and Factor IX promoters in both hepatoma cells and pre-B ALL cells [14].
• We constructed chimeric genes in which the sequences at the 5' end of the E2A, E3, and E4 regions were fused to the structural sequences of either the herpes simplex virus thymidine kinase gene, the bacterial gene encoding the enzyme neomycin phosphotransferase, or the chloramphenicol acetyltransferase gene [15].
• In the adenovirus type 2 (Ad2)-transformed hamster cell line HE3, the integrated late E2A promoter of Ad2 DNA is inactive, is methylated at all three 5'-CCGG-3' sequences, and can be reactivated by growing the cells in the presence of 50 microM 5-azacytidine (5-azaC) [16].

Biological context of TCF3

• The human AES gene was further localized by fluorescence in situ hybridization to chromosome band 19p13.3 near the transcription factor 3 (TCF3) gene [17].
• Apoptosis promoted by up-regulation of TFPT (TCF3 fusion partner) appears p53 independent, cell type restricted and cell density influenced [18].
• Two complementary DNAs were isolated that encode proteins, denoted ITF-1 and ITF-2, that are expressed in a variety of cell types and bind the microE5/kappa 2 motif found in both heavy and kappa light chain enhancers [19].
• We previously reported that the E2A-HLF fusion protein protects interleukin-3 (IL-3)-dependent lymphoid cells from apoptosis caused by cytokine starvation [4].
• E2A-HLF functioned as a potent trans activator of reporter gene expression from a plasmid that contained the consensus DNA-binding sequence [20].

Anatomical context of TCF3

• Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells [3].
• Furthermore, a heterodimeric complex containing ABF-1 and E2A can be detected in EBV-immortalized lymphoblastoid cell lines [21].
• The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells [20].
• Expression of E2A and FGFR3 was seen at the location of osteoblast differentiation in the calvaria of mouse embryos, implicating bHLH molecules in physiological osteoblast differentiation [22].
• Immunohistochemistry of placental tissues and differentiating villous explant cultures showed that expression of TCF-3/4 strongly increased in invading trophoblasts [23].

Associations of TCF3 with chemical compounds

• Fourth, C3H10T1/2 cells expressing antisense E2A transcripts contain low levels of E2A gene products and display less terminal muscle differentiation when infected with retroviral MyoD or when challenged to differentiate with 5-azacytidine treatment [24].
• HEN1 encodes a 20-kDa polypeptide (pp20HEN1) that is phosphorylated exclusively at serine residues and forms dimeric bHLH complexes either by self-association or by heterologous interaction with the E2A gene products (E12 or E47) [25].
• Moreover, overexpression of 31-kDa led to cell death that could be inhibited by treatment with the caspase inhibitor ZVAD-fluoromethyl ketone or by ectopic expression of E2A or p21(Waf1/Cip1) [26].
• The coactivator Bridge-1 (PSMD9) regulates the transcriptional activation of glucose-responsive enhancers in the insulin gene in a dose-dependent manner via PDZ domain-mediated interactions with E2A transcription factors [27].
• Moreover, in cell line HE2, the integrated, heavily methylated late E2A promoter has been shown by the genomic sequencing technique to contain 5-methyldeoxycytidine residues, not only in all 5'-CG-3' dinucleotides but also in a 5'CA-3' and a 5'-CT-3' dinucleotide sequence [28].

Physical interactions of TCF3

• The gene (E2A) for enhancer binding transcription factors E12 and E47 maps to the t(1;19) chromosomal translocation breakpoint in pre-B cell leukemias [29].
• The t(1;19) translocation results in the production of a chimeric transcription factor containing the N-terminal transactivation domain of E2A fused to the C-terminal DNA-binding homeodomain of Pbx1 [30].
• These differences were directly attributable to loss of an HLF ancillary DNA-binding domain in all E2A-HLF chimeras and were further exacerbated by a zipper mutation in one isolate [31].
• These two transcription factors can recognize the same DNA motif in the adenovirus E2A promoter and can bind to it by themselves or in association with RB [32].
• Competition experiments revealed that these three classes are functionally equivalent to each other and to the E2F/DRTF-1 binding site in the adenovirus E2A promoter [32].

Regulatory relationships of TCF3

• We found that the minimal p21/waf1 promoter (-49 to +49 sequence) was activated by Tax and the minimal promoter contained two E2A transcription factor binding sites located between the TATA box and the initiation site [33].
• Expression of BHLHB1 dramatically inhibited E2A-mediated transcription activation in NIH 3T3 fibroblasts and Jurkat T cells [34].
• TFE3 can only stimulate enhancer activity in the presence of ITF-1 or in the absence of a microE5 motif [35].
• The inhibition model postulates that Tal1 interferes with the tumor-suppressing function of E2A [36].
• Finally, cotransfection of rPM-Scl and E47 specifically increased the promoter activity of a luciferase reporter construct containing an E box and did not affect the basal activity of the reporter construct. rPM-Scl appears to be a novel non-HLH-interacting partner of E12/E47 that regulates E2A protein transcription [37].

Other interactions of TCF3

• The complementary DNAs are the products of distinct genes, yet both ITF-1 and ITF-2 are structurally and functionally similar [19].
• Thus, the malignant properties of TAL1 may be due to obligate interaction with the E2A polypeptides [3].
• Separate expression of BETA2, E2A, or PDX1 led to modest (<10-fold) activation of the insulin promoter, whereas co-expression of the three proteins produced synergistic, high level activation (160-fold) [38].
• Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter [38].
• The 19p13 breakpoint of one tumor was mapped to a location between the INSR and the TCF3 loci [2].

Analytical, diagnostic and therapeutic context of TCF3

• We have now applied two independent methods, the two-hybrid procedure and co-immunoprecipitation analysis, to demonstrate that TAL1 and E2A polypeptides also associate in vivo [3].
• Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system [39].
• In quiescent, freshly purified HPCs, Id2 mRNA is detected by reverse transcriptase-polymerase chain reaction (RT-PCR), whereas TAL1 and E2A mRNAs are not [7].
• In all PCR-positive cases the junction of E2A and PBX1 coding sequences occurred at precisely the same location as demonstrated by hybridization of PCR products with a fusion site-specific detection oligonucleotide [40].
• A new E2A-containing microE2-binding species (P-E2A) was identified in plasma cells by using electrophoretic mobility shift assays [41].

References