Modeling Wnt/β-Catenin Target Gene Expression in APC and Wnt Gradients Under Wild Type and Mutant Conditions

Abstract

The Wnt/β-catenin pathway is involved in the regulation of a multitude of physiological processes by controlling the differential expression of target genes. In certain tissues such as the adult liver, the Wnt/β-catenin pathway can attain different levels of activity due to gradients of Wnt ligands and/or intracellular pathway components like APC. How graded pathway activity is converted into regionally distinct patterns of Wnt/β-catenin target gene expression is largely unknown. Here, we apply a mathematical modeling approach to investigate the impact of different regulatory mechanisms on target gene expression within Wnt or APC concentration gradients. We develop a minimal model of Wnt/β-catenin signal transduction and combine it with various mechanisms of target gene regulation. In particular, the effects of activation, inhibition, and an incoherent feedforward loop (iFFL) are compared. To specify activation kinetics, we analyze experimental data that quantify the response of β-catenin/TCF reporter constructs to different Wnt concentrations, and demonstrate that the induction of these constructs occurs in a cooperative manner with Hill coefficients between 2 and 5. In summary, our study shows that the combination of specific gene regulatory mechanisms with a time-independent gradient of Wnt or APC is sufficient to generate distinct target gene expression patterns as have been experimentally observed in liver. We find that cooperative gene activation in combination with a TCF feedback can establish sharp borders of target gene expression in Wnt or APC gradients. In contrast, the iFFL renders gene expression independent of gradients of the upstream signaling components. Our subsequent analysis of carcinogenic pathway mutations reveals that their impact on gene expression is determined by the gene regulatory mechanism and the APC concentration of the cell in which the mutation occurs.

A hypermorphic epithelial beta-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations

“…Indeed, in Bcat mice we detected transcriptional activation of only a subset of Wnt/β-catenin target genes, including some specific for Paneth cells. This is consistent with models suggesting that different gene promoters require different levels of Wnt/β-catenin pathway activation for efficient transcription ( Darken and Wilson, 2001 ; Albuquerque et al, 2010 ) and with mathematical calculations that the combination of gene-specific regulatory mechanisms with gradients of β-catenin and Apc functions are sufficient to confer distinct target gene expression patterns ( Benary et al, 2013 ).…”

Activation of the Wnt/β-catenin signaling pathway may contribute to cervical cancer pathogenesis via upregulation of Twist

“…The Wnt/β-catenin signaling pathway has been reported to be involved in tumorigenesis of a number of types of cancer, including cervical, ovarian, breast and oral cancer (14). In addition, a number of studies have suggested roles for the Wnt/β-catenin signaling pathway-associated proteins β-catenin, GSK3β, adenomatous polyposis coli protein, Wnt and T-cell factor/lymphoid enhancer factor (TCF/LEF) in cervical cancer progression (15,16).…”

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

“…(b) Even in the presence of APC mutations, blockade of WNT ligands triggers apoptosis or growth inhibition 40,113,118 . (c) β-Catenin fold induction is essential for the activation of β-catenin target genes [119][120][121] . (d) Increased AXIN1 by Tankyrase inhibitor suppresses cell proliferation of cancer cells where Wnt/β-catenin signaling is genetically hyperactive 43,90,93,95,122 .…”