MicroRNA roles in beta-catenin pathway

Abstract

β-catenin, a key factor in the Wnt signaling pathway, has essential functions in the regulation of cell growth and differentiation. Aberrant β-catenin signaling has been linked to various disease pathologies, including an important role in tumorigenesis. Here, we review the regulation of the Wnt signaling pathway as it relates to β-catenin signaling in tumorigenesis, with particular focus on the role of microRNAs. Finally, we discuss the potential of β-catenin targeted therapeutics for cancer treatment.

Figure 1

Visualization of β-catenin interaction network. 10018 articles describing putative interactions between β-catenin and other genes were identified through querying Pubmed with: (catenin or CTNNB or CTNNB1) and ("1980/01/01"[PDAT]: "2009/05/24"[PDAT]) and text mining. 213 genes (including Tcf4 and Lef, ect.) formed a complex with β-catenin (interaction relations is associate, bind, etc.) and β-catenin interaction network was constructed by Cytoscape.

Figure 2

Upstream regulators of β-catenin transcriptional activity. For details see the text. EGFR, AKT1, miR-315 and miR-135a/b upregulate β-catenin transcriptional activity, whereas miR-200a, miR-21 and miR-8 downregulate β-catenin transcriptional activity.

Figure 3

Coregulators of β-catenin transcriptional ativity. Via interacting with the β-catenin/Tcf/Lef complex, HDAC3/6, c-Jun, TNIK and Snail upregulate β-catenin transcriptional activity (up), whereas HDAC1/2, CtBP, Groucho, KLF4, MAD2B and VentX downregulate β-catenin transcriptional activity (down).

Figure 4

Positive feedback loops between β-catenin and downstream targets. The β-catenin/Tcf complex directly binds to binding element site (TBE) of the AKT1 and STAT3 gene promoter. In turn AKT1 activation induces β-catenin phosphorylation at Ser552 directly or by GSK-3β phosphorylation and STAT3 activation increases the nuclear accumulation of β-catenin, thereby increasing β-catenin nuclear translocation and enhancing transcriptional activity. In addition, the E2F1 promoter activity is repressed by overexpression of β-catenin/Tcf, and E2F1 inhibites β-catenin transcription directly or via upregulation of Siah1.

Figure 5

Novel molecular regulation of Wnt/β-catenin pathway. Particular Wnt/β-catenin signaling pathways affected by upstream regulators, coregulators and downstream targets are described in detail in the review.