A transcriptional response to Wnt protein in human embryonic carcinoma cells

Abstract

BackgroundWnt signaling is implicated in many developmental decisions, including stem cell control, as well as in cancer. There are relatively few target genes known of the Wnt pathway.ResultsWe have identified target genes of Wnt signaling using microarray technology and human embryonic carcinoma cells stimulated with active Wnt protein. The ~50 genes upregulated early after Wnt addition include the previously known Wnt targets Cyclin D1, MYC, ID2 and βTRCP. The newly identified targets, which include MSX1, MSX2, Nucleophosmin, Follistatin, TLE/Groucho, Ubc4/5E2, CBP/P300, Frizzled and REST/NRSF, have important implications for understanding the roles of Wnts in development and cancer. The protein synthesis inhibitor cycloheximide blocks induction by Wnt, consistent with a requirement for newly synthesized β-catenin protein prior to target gene activation. The promoters of nearly all the target genes we identified have putative TCF binding sites, and we show that the TCF binding site is required for induction of Follistatin. Several of the target genes have a cooperative response to a combination of Wnt and BMP.ConclusionsWnt signaling activates genes that promote stem cell fate and inhibit cellular differentiation and regulates a remarkable number of genes involved in its own signaling system.

Atherosclerotic Calcification: Wnt Is the Hint

“…Msx2 enhances Wnt signaling through the upregulation of several Wnt ligands98 and the downregulation of dickkopf homologue 1,99 a canonical Wnt pathway antagonist. Indeed, Msx2 and Wnt seem to regulate each other's expression in a bidirectional way 100, 101. For instance, Msx2 stimulates Wnt‐dependent T‐cell factor/lymphoid enhancer‐binding factor transcription, increases β‐catenin nuclear localization, and increases the expression of canonical Wnt ligands, Wnt3a and Wnt7, and noncanonical ligand, Wnt5.…”

Real-time imaging of β-catenin dynamics in cells and living mice

“…In this phosphorylated state, ␤-cat is ubiquitinated and consequently degraded via the proteasome (5). In the presence of Wnt, the destruction complex is inhibited (3,6), hypophosphorylated ␤-cat is stabilized in the cytoplasm and translocates to the nucleus, where it forms a complex with T cell factor (TCF) or lymphoid enhancer-binding factor (LEF) (7) to activate transcription of Ͼ50 genes, including c-MYC, cyclin D1, gastrin, and matrilysin (8). A third population of ␤-cat resides in a membranous complex with E-cadherin and ␣-catenin and plays a pivotal role in intercellular adhesion (1,4).…”

Regulating the Balance between Peroxisome Proliferator-activated Receptor γ and β-Catenin Signaling during Adipogenesis

“…A major component of the Wnt pathway is the versatile protein, ␤-catenin, which fulfills several functions during the growth and differentiation of various cells (2).…”

“…GSK3␤ phosphorylates ␤-catenin on serine 33, serine 37, and threonine 41 following a priming phosphorylation by casein kinase I on serine 45, which targets ␤-catenin for degradation by the ubiquitin-proteasomal system (11)(12)(13)(14)(15)(16). Inhibition of GSK3␤ activity by Wnt signaling or activation of Akt/PKB leads to accumulation of ␤-catenin in the cytoplasm and its subsequent translocation to the nucleus and activation of target genes (2,(17)(18)(19)(20).…”