Disease relevance of pan

• Humans possess two Pygo proteins, both of which are required for TCF-mediated transcription in colorectal cancer cells [1].
• In APC-positive colon carcinomas and melanomas, dominant mutations in beta-catenin render it indestructable, providing an alternative mechanism to activate transcription of TCF target genes inappropriately [2].
• Second, recombinant LEF-1 is shown to activate HIV-1 transcription on chromatin-assembled DNA in vitro [3].

High impact information on pan

• Its activation entails the association of beta-catenin with nuclear TCF/LEF proteins and results in transcriptional activation of target genes [4].
• Evidence that Armadillo transduces wingless by mediating nuclear export or cytosolic activation of Pangolin [5].
• A mutation in dTCF, the DNA-binding protein required in Arm-mediated signal transduction, can eliminate the cell death without rescuing the differentiation defect in D-APC mutants [6].
• Uncoupling of these two Arm-induced processes suggests a novel role for the Arm/dTCF complex in the activation of apoptosis [6].
• Finally, efficient transcriptional stimulation by LEF-1 in the midgut depends also on the decapentaplegic response sequence and is limited spatially by decapentaplegic signaling [7].

Biological context of pan

• LEF-1 is an additional transcription factor that mediates transactivation of TCR enhancers [8].
• We investigated this region genetically and molecularly by use of an enhancer trap line (IA5), where the P-element was found to be inserted into the first intron of pan [9].
• Using genetic methods in Drosophila, we define a new segment polarity gene, pangolin (pan), and show that its product is required in vivo for Wg signal transduction in embryos and in developing adult tissues [10].
• Wnt signaling inhibits its phosphorylation and degradation; this allows it to associate with TCF/LEF factors bound to Wnt target genes and to stimulate their transcription by recruiting chromatin modifying and remodeling factors [11].
• Using reporter gene assays, we show that the two proteins antagonistically influence the transactivation potential of the beta-catenin-TCF complex [12].

Anatomical context of pan

• Here, we report that Pygo is associated constitutively with dTCF target genes in Drosophila salivary glands and tissue-culture cells [11].
• Here, we analyse the mode of action of Pan, Arm, Lgs, and Pygo in Drosophila cultured cells [13].
• We show that this sequence is recognized by the murine transcription factor LEF-1 (lymphocyte enhancer binding factor 1) in a ternary complex with armadillo protein, the cytoplasmic target of the wingless signaling pathway [7].
• Wingless- mediated transcriptional activation is conferred by Drosophila: T-cell factor (dTCF) and its co-activator Armadillo, but the nuclear factors mediating transcriptional repression are unknown [14].
• Consistent with the demonstrated role of the Wnt-beta-catenin-LEF/TCF signaling pathway in mammalian skin development, mpygo2 expression was detected in the developing epidermis and hair follicles, which suggests that mpygo2 might mediate the effect of this signaling pathway in mouse skin [15].

Associations of pan with chemical compounds

• Wingless-Independent Association of Pygopus with dTCF Target Genes [11].
• We provide evidence that together these four proteins form a 'chain of adaptors' linking the NH2-terminal homology domain (NHD) of Pygo to the DNA-binding domain of Pan. We show that the NHD has potent transcriptional activation capacity, which differs from that of acidic activator domains and depends on a conserved NPF tripeptide [13].
• None of these transcription inhibitors (CT-ARM, ICAT, or sulindac) could disrupt the LEF-1-beta-cat complex after it was stably bound to chromatin [16].

Physical interactions of pan

• It is generally thought that beta-catenin/Armadillo is a transcriptional coactivator when bound to TCF in the nucleus and that this function is mediated by its C terminus [17].

Regulatory relationships of pan

• However, recent findings in Drosophila indicated that Armadillo may activate dTCF in the cytoplasm [17].

Other interactions of pan

• We show that this difference cannot be attributed to maternally provided pan product, indicating that a Pan repressor function usually prevents the expression of embryonic Wg targets [18].
• pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila [10].
• By transient luciferase expression assays and band mobility shift assays, we demonstrated the PCNA gene to be a direct target gene for the Armadillo/Pangolin complex [19].
• Drosophila RpS3a, a novel Minute gene situated between the segment polarity genescubitus interruptus and dTCF [20].
• The nuclear mediators of the two signaling pathways, Cubitus interruptus and Pangolin, function as activator and symmetry-breaking repressor of stripe expression, respectively [21].

Analytical, diagnostic and therapeutic context of pan

• In mammalian cells, coexpressed LEF-1 and beta-catenin form a complex that is localized to the nucleus and can be detected by immunoprecipitation [22].
• Microinjection of LEF-1 into XenoPus embryos induces axis duplication, which is augmented by interaction with beta-catenin [22].

References