Cell cycle control of Wnt/β‐catenin signalling by conductin/axin2 through CDC20

Abstract

Wnt/b-catenin signalling regulates cell proliferation by modulating the cell cycle and is negatively regulated by conductin/axin2/ axil. We show that conductin levels peak at G2/M followed by a rapid decline during return to G1. In line with this, Wnt/b-catenin target genes are low at G2/M and high at G1/S, and b-catenin phosphorylation oscillates during the cell cycle in a conductindependent manner. Conductin is degraded by the anaphasepromoting complex/cyclosome cofactor CDC20. Knockdown of CDC20 blocks Wnt signalling through conductin. CDC20-resistant conductin inhibits Wnt signalling and attenuates colony formation of colorectal cancer cells. We propose that CDC20-mediated degradation of conductin regulates Wnt/b-catenin signalling for maximal activity during G1/S.

The S-G2 phase enriched β-catenin/TCF complex ensures cell survival and cell cycle progression

“…The capacity that cells have to produce or allow a higher level of b-catenin-TCF complex during the S-G2 phase might therefore provide a basis for the ligand stimulation during the G2-M phase, as observed previously by Davidson and colleagues (Davidson et al, 2009). The accumulation of cytosolic b-catenin during the S-G2 phase might thus result in the elevation of b-catenin that is phosphorylated at residues S33, S37 and T41 in SW480 colon cancer cells (Hadjihannas et al, 2012). We also noted that the oscillation pattern of the level of nuclear b-catenin and that of the b-catenin-TCF complex were similar, although not identical (Fig.…”

“…In 1999, the cytoplasmic level of bcatenin protein was found to increase from the G1 to the S phase, and it was suggested that Wnt-b-catenin signaling might function during the G1/S transition (Orford et al, 1999). CDC20-mediated degradation of the Wnt inhibitor AXIN2 during G1-S has also been observed, further supporting a possible peak of Wnt during this time window (Hadjihannas et al, 2012). However, the level of soluble b-catenin, which is not associated with the cytoskeleton and plasma membrane, in synchronized cells is found at the maximal level in G2-M cells (Olmeda et al, 2003).…”

“…Furthermore, G2-M-specific cyclin Y and CDK14 imposes priming phosphorylation on the Wnt receptor LRP6, again suggesting that Wnt signaling peaks at G2-M (Davidson et al, 2009). The discrepancy concerning the expression levels of Wnt target genes during different cell cycle stages has further added complexity to this issue, for example, MYC is found to be elevated at G1 whereas LGR5 and AXIN2 are upregulated at G2 (Hadjihannas et al, 2012). Here, we directly focused on the final executor of canonical Wnt signaling, the nuclear b-catenin-TCF complex, and observed its enrichment in S-G2 cells.…”

“…Paradoxically, mRNA levels of Wnt target genes, such as AXIN2 (a negativefeedback regulator also known as conductin/axil) and LGR5 [a coreceptor for R-spondin1 and a positive modulator of b-catenin signaling (de Lau et al, 2011;Glinka et al, 2011)], peak at the G2-M phase, whereas MYC mRNA accumulates in the G1-S phase (Rabbitts et al, 1985;Hadjihannas et al, 2012). In the same report, it was also shown that phosphorylated b-catenin, which should be subjected to ubiquitylation and degradation, was enriched during the S-G2 phase (Hadjihannas et al, 2012). From these results, it was concluded that Wnt-b-catenin signaling is relatively low in the G2 phase.…”

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…To determine whether increased β-catenin signaling sensitizes cells to DNA damage, we expressed constitutively active β-catenin (S33Y) in U2OS cell. These cells, unlike SW480 cells, do not rely on aberrant WNT signaling for cell growth (Hadjihannas et al, 2012). β-Catenin (S33Y) expression resulted in an increase in the number of DNA lesions compared to the number in mock-transfected cells (Fig.…”