Disease relevance of Tcf4

• Inhibition of beta-catenin/Tcf signaling by ectopic expression of dominant negative Tcf4 resulted in significant inhibition of growth in squamous cell carcinoma cells [1].
• The high levels of Tcf-4 expression in mammary epithelium and mammary carcinomas may also indicate a role in the development of this tissue and breast carcinoma [2].
• We recently demonstrated that beta-cat/Tcf-4 regulates transcription of ET-1 in colon cancer cells [3].

Psychiatry related information on Tcf4

• MyoD activity was also inhibited by Id, a HLH protein, and this inhibition was reversed by the addition of excess E12 or MITF-2A [4].
• Haploinsufficiency of TCF4 causes the Pitt-Hopkins mental retardation syndrome, underscoring the important role for this protein in neural development [5].

High impact information on Tcf4

• We conclude that the genetic program controlled by Tcf-4 maintains the crypt stem cells of the small intestine [6].
• However, targeted gene inactivations of Lef1, Tcf1, or Tcf4 in the mouse do not produce phenotypes that mimic any known Wnt mutation [7].
• E2A, HEB, E2-2, and daughterless are basic helix-loop-helix (bHLH) proteins that play key roles in multiple developmental pathways [8].
• To gain new insight into the role of T-cell factors (or Tcf's) during development, we analysed Tcf4 and Tcf1 compound null embryos [9].
• We have previously shown that E-boxes and the ubiquitously expressed class I basic helix-loop-helix (bHLH) proteins, including E2-2 and E12, are important in regulation of the SMC differentiation marker gene, the SM alpha-actin gene [10].

Biological context of Tcf4

• Transient transfection of F9 cells with an expression vector harboring a dominant-negative mutant of Tcf4 resulted in the attenuation of both the increase in Lef-Tcf-sensitive transcription and formation of primitive endoderm in response to the morphogen [11].
• Physical and functional interactions between the transcriptional inhibitors Id3 and ITF-2b. Evidence toward a novel mechanism regulating muscle-specific gene expression [12].
• Moreover, while ITF-2b inhibited the creatine kinase promoter, it acted as a weak transactivator on an artificial promoter consisting of three tandem copies of the consensus myogenic factor DNA binding site [12].
• This inhibitory activity required the N-terminal 83 amino acids since MITF-2A showed no inhibitory activity, and a mutant MITF-2B with deletion of the N-terminal 83 amino acids failed to inhibit MyoD-mediated transcriptional activation [4].
• Overexpression of ITF-2 significantly reduced Id-1-stimulated proliferation and apoptosis [13].

Anatomical context of Tcf4

• Tcf4-deficient mouse embryos show abrogation of Cdx1 protein in the small intestinal epithelium, making Tcf4 the likely candidate to transduce Wnt signal in this part of gut [14].
• We propose that Tcf4-expressing cells establish a prepattern in the limb mesoderm that determines the sites of myogenic differentiation and thus establishes the basic pattern of limb muscles [15].
• Tcf-4 expression levels increased dramatically on the villi of more highly developed (week 22) fetal small intestine [2].
• Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium [2].
• In contrast to E2A, E2-2 and HEB are not essential for the establishment of the B-cell lineage [16].

Regulatory relationships of Tcf4

• A splice variant of the ITF-2 transcript encodes a transcription factor that inhibits MyoD activity [4].
• E12 expression inhibited and ITF2b augmented activity in A7R5 cells, but had no effect in NIH3T3 cells [17].

Other interactions of Tcf4

• Thus, differentially spliced transcripts of mouse ITF-2 encode different proteins that appear to dimerize with MyoD and activate or repress transcription [4].
• Neither MITF-2A nor -2B transactivated the cardiac alpha-actin promoter, which contains an E box, when transfected into nonmuscle cells [4].
• In an investigation of the molecular mechanisms controlling these patterns, we have recently shown that binding of the transcription factor SEF-2 to a novel initiator element in the SSTR-2 promoter is essential for SSTR-2 gene expression [18].
• Decreases in the mRNA expression of two transcription factors associated with cancer, hypoxia-induced factor 1 alpha (HIF1 alpha) and transcription factor 4 (TCF4), were confirmed by quantitative RT-PCR [19].
• ME2 is expressed in the cerebral cortex, Purkinje and granule cell layers of the cerebellum, olfactory neuroepithelium, pyramidal cells of hippocampal layers CA1-CA4, and in the granular cells of the dentate gyrus [20].

Analytical, diagnostic and therapeutic context of Tcf4

• Immunohistochemistry performed with the Tcf 4- specific monoclonal antibody revealed high levels of expression in normal intestinal and mammary epithelium and carcinomas derived therefrom [2].
• Northern blots confirm the induction of SEF2 [21].
• In situ hybridization analyses reveal that ME1a and ME2 are characterized by distinguishable patterns of expression in areas of the adult mouse brain where neuronal plasticity occurs [22].
• A panel of monoclonal antibodies (mAbs) specific to type 1 (SEF 2) fimbriae of S. enteritidis was produced using crude and HPLC purified preparations of SEF 21 fimbriae [23].
• The signal transducer and activator of transcription factor 4 (STAT4) pathway mediates the intracellular effects of interleukin-12 (IL-12), leading to the production of gamma interferon, induction of a T helper type 1 response, and increased natural killer cell cytotoxicity [24].

References