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Abstract
Aberrant Wnt signaling has been implicated in a wide variety of cancers and many components of the Wnt signaling network have now been identified. Much less is known, however, about how these proteins are coordinately regulated. Here, a broad, quantitative, and dynamic study of Wnt3a-mediated stimulation of HEK 293 cells revealed two phases of transcriptional regulation: an early phase in which signaling antagonists were downregulated, providing positive feedback, and a later phase in which many of these same antagonists were upregulated, attenuating signaling. The dynamic expression profiles of several response genes, including MYC and CTBP1, correlated significantly with proliferation and migration (P<0.05). Additionally, their levels tracked with the tumorigenicity of colon cancer cell lines and they were significantly overexpressed in colorectal adenocarcinomas (P<0.05). Our data highlight CtBP1 as a transcription factor that contributes to positive feedback during the early phases of Wnt signaling and serves as a novel marker for colorectal cancer progression.
Highlights
Wnt proteins constitute a family of highly conserved growth factors [1] that mediate a wide range of biological processes, including proliferation, migration, and differentiation
Most notably, activating mutations in components of the canonical Wnt signaling pathway are observed in .90% of colorectal cancers [6], and colorectal cancer is currently the second leading cause of cancer-related deaths in the United States [7]
The canonical Wnt signaling pathway is activated when a Wnt ligand binds to the transmembrane receptors frizzled (Fzd) and low-density lipoprotein receptor-related protein (LRP) [8,9]
Summary
Wnt proteins constitute a family of highly conserved growth factors [1] that mediate a wide range of biological processes, including proliferation, migration, and differentiation. To investigate how Wnt signaling proteins interrelate to control normal cellular functions such as proliferation and migration, we used serum-starved human embryonic kidney (HEK) 293 cells to follow the transcript levels of virtually every protein that has been implicated in Wnt signaling over a 24-h time course of stimulation with Wnt3a.
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