Disease relevance of Tcfe2a

• In addition, mice deficient for E2A are highly susceptible to thymic lymphoma [1].
• It was discovered as a fusion with the E2A gene after chromosomal translocations in a subset of acute leukemias [2].
• Pan-1 and Pan-2 were expressed in Escherichia coli, and a purification scheme was developed [3].
• Ectopic expression of HLF as an E2A-HLF fusion protein in t(17;19)-positive human pro-B cell acute lymphoblastic leukemias is believed to promote malignancy by interfering with apoptosis [4].
• The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL) [5].

Psychiatry related information on Tcfe2a

• MyoD activity was also inhibited by Id, a HLH protein, and this inhibition was reversed by the addition of excess E12 or MITF-2A [6].

High impact information on Tcfe2a

• We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells [7].
• Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice [8].
• Embryos with homozygous mutations in AML1 showed normal morphogenesis and yolk sac-derived erythropoiesis, but lacked fetal liver hematopoiesis and died around E12 [9].
• These data suggest a crucial role for E2A products as central regulators in early B cell differentiation [10].
• E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements [10].

Chemical compound and disease context of Tcfe2a

• A fusion construct composed of E2A and the Escherichia coli DNA adenosine methyltransferase (E47Dam) was subcloned in lentivirus vectors and used to transduce precursor B-cell and myeloid progenitor cell lines [11].
• The chloramphenicol acetyltransferase gene under the control of the late E2A promoter of adenovirus type 2 (Ad2) was introduced as transgene into the B6D2F1 mouse strain with mixed genetic background and became extensively de novo methylated [12].
• There was also a transient twofold increase in mrf4 transcripts by dexamethasone treatment in dividing cells, while no changes were detected in the levels of Id, E12, or TnC messages [13].
• Diallyl sulfide (DAS), an inhibitor of CYP2E1, also protected against the cisplatin toxicity in the E47 cells [14].
• The early expression of voltage-activated chloride channels of large unitary conductance (450 pS in symmetrical 140 mM KCl) was demonstrated using patch-clamp techniques in two preparations: (i) neural crest cells isolated from 9-day-old (E9) mouse embryos and (ii) acutely isolated dorsal root ganglion cells isolated from E12 mouse embryos [15].

Biological context of Tcfe2a

• E12 and E47 are two helix-loop-helix transcription factors that arise by alternative splicing of the E2A gene [10].
• Here we have isolated E2A-deficient bone marrow-derived cells that have the ability to grow long-term in vitro and coexpress, at low levels, regulators of different hematopoietic cell lineages [16].
• Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A [17].
• In the absence of E47 activity, positive selection of both major histocompatibility complex (MHC) class I- and class II-restricted T cell receptors (TCRs) is perturbed [18].
• However, in addition to the HLH region, E2A contains two inhibitory regions over-lapping with the main transcriptional activation domains [19].

Anatomical context of Tcfe2a

• EBF and E2A synergistically upregulate transcription of endogenous B cell-specific genes in a non-B cell line [20].
• E2A proteins are essential for the development of B cells beyond the progenitor cell stage [16].
• Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent [16].
• T cell development in E2A-deficient mice is partially arrested before lineage commitment [21].
• Thus we propose that Notch regulates lymphocyte differentiation by controlling E2A protein turnover [22].

Associations of Tcfe2a with chemical compounds

• E2A protein, but not mRNA, levels were reduced in pro-B cells upon culture in vitro with IL-7 + rmSCF [23].
• Turnover of E2A proteins was assessed following cycloheximide treatment [23].
• The transactivation function of VDIR was further potentiated by activated-PKA signaling through phosphorylation of serine residues in the transactivation domains, with the recruitment of a p300 histone acetyltransferase co-activator [24].
• Degradation of E47 was effectively blocked by the proteasome inhibitor lactacystin as well as calpain I and II inhibitors; E2A proteins were also shown to undergo ubiquitination [25].
• Critical role for a single leucine residue in leukemia induction by E2A-PBX1 [26].

Physical interactions of Tcfe2a

• Interaction assays in yeast and in vitro demonstrate that MATH4A interacts efficiently with both MASH1 and the ubiquitous bHLH protein E12 [27].
• However, stimuli that mimic pre-T cell receptor (TCR) signaling in committed T cell precursors inhibit E47 DNA-binding activity and induce the bHLH inhibitor Id3 through a mitogen-activated protein kinase kinase-dependent pathway [21].
• Retroviral transduction of Id3 also repressed the SRG3 expression by inhibiting the E box binding activity of the E2A/HEB complex [28].
• The age-related decrease in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrow-derived B cell precursors [29].
• Gel mobility shift assays demonstrate that Twist can bind to the muscle creatine kinase E-box and inhibit DNA binding of heterodimers of E12 with myogenic bHLH transcription factors like MyoD [30].

Enzymatic interactions of Tcfe2a

• Closer examination indicates that E47 is phosphorylated in vitro by p38, and deletion analysis predicts that the critical amino acid(s) phosphorylated by p38 lie outside of the minimal transcriptional activation domains [31].

Regulatory relationships of Tcfe2a

• The capacity to respond to SCF may influence the levels of E2A during B-cell development [23].
• Conversely, knocking down CHIP with small interfering RNA alleviates Notch-induced E47 degradation [32].
• We next investigated the signal transduction pathways controlling E2A mRNA expression and stability and found that p38 MAPK regulates E2A mRNA expression through increased mRNA stability and is down-regulated in aged activated B cells [33].
• Transcriptional repression by Fos and Jun is specific to myogenic HLH proteins and is not observed with the widely expressed HLH protein E47, which recognizes the same DNA sequence [34].
• These observations support a model in which the upregulation of pre-TCR signalling seems to be the prerequi-site for Notch3-induced inhibition of E2A, thus leading to the development of lymphoma in Notch3 transgenic mice [35].

Other interactions of Tcfe2a

• These data suggest a molecular basis for the hierarchical dependence of Pax5 function on EBF and E2A in B lymphocyte development [36].
• EBF and the basic helix-loop-helix transcription factor E47 each contributed to epigenetic modifications of the mb-1 promoter, including CpG demethylation and nucleosomal remodeling [36].
• These findings identify a novel pro-myogenic role of p38 in regulating the formation of functional MyoD/E47 heterodimers that are essential for myogenesis [37].
• When E47 lacking the HLH domain was overexpressed, Id could no longer reverse growth inhibition [19].
• IL-7Ralpha and E47: independent pathways required for development of multipotent lymphoid progenitors [38].

Analytical, diagnostic and therapeutic context of Tcfe2a

• We have now generated E2A (-/-) mice by gene targeting [10].
• Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system [39].
• To further understand the mechanism underlying E2A ubiquitination and degradation, we conducted a yeast two-hybrid screen and identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as an E47 binding protein [32].
• We also obtained evidence for extensive collaborative actions of EBF and E47 even though microarray analysis of hematopoetic progenitor cells ectopically expressing these proteins suggested that they activated only a subset of pre-B cell restricted genes [40].
• From titrations of MyoD-dansyl with E12 at 100 mM KCl, a free energy of heterodimerization of 8.7 (+0.4/-2.4) kcal/mol was recovered using rigorous confidence limit testing [41].

References