β-Catenin Regulation during the Cell Cycle: Implications in G2/M and Apoptosis

Abstract

Beta-catenin is a multifunctional protein involved in cell-cell adhesion and Wnt signal transduction. Beta-catenin signaling has been proposed to act as inducer of cell proliferation in different tumors. However, in some developmental contexts and cell systems beta-catenin also acts as a positive modulator of apoptosis. To get additional insights into the role of beta-catenin in the regulation of the cell cycle and apoptosis, we have analyzed the levels and subcellular localization of endogenous beta-catenin and its relation with adenomatous polyposis coli (APC) during the cell cycle in S-phase-synchronized epithelial cells. Beta-catenin levels increase in S phase, reaching maximum accumulation at late G2/M and then abruptly decreasing as the cells enter into a new G1 phase. In parallel, an increased cytoplasmic and nuclear localization of beta-catenin and APC is observed during S and G2 phases. In addition, strong colocalization of APC with centrosomes, but not beta-catenin, is detected in M phase. Interestingly, overexpression of a stable form of beta-catenin, or inhibition of endogenous beta-catenin degradation, in epidermal keratinocyte cells induces a G2 cell cycle arrest and leads to apoptosis. These results support a role for beta-catenin in the control of cell cycle and apoptosis at G2/M in normal and transformed epidermal keratinocytes.

Interaction between Tumor Suppressor Adenomatous Polyposis Coli and Topoisomerase IIα: Implication for the G2/M Transition

“…Activated Wnt signaling resulting from stabilized ␤-catenin was recently reported to contribute to chromosome instability (Aoki et al, 2007) and lead to G2 arrest (Olmeda et al, 2003). Thus, we predicted that the abnormal nuclear morphology seen in cells expressing M2-APC was dependent on M2-APC association with and stabilization of nuclear ␤-catenin.…”

“…APC locates near centrosomes during early and late stages of mitosis and has also been implicated in maintenance of chromatin structure (Olmeda et al, 2003;Huang et al, 2007). Therefore, we cannot exclude the possibility that both APC and topo II␣ provide multiple functions throughout the G2/M transition.…”

“…Overexpression of APC in NIH3T3 fibroblasts and colon cancer cell lines leads to G1 cell cycle arrest (Ishidate et al, 2000;Heinen et al, 2002), presumably by repressing transcription of Wnt targets such as cyclin D1. APC may also participate directly in mitosis because it is transiently hyperphosphorylated in the M phase of the cell cycle (Bhattacharjee et al, 1996), accumulates at the microtubule-organizing center (Olmeda et al, 2003), and associates with the kinetochore in dividing cells (Fodde et al, 2001;Kaplan et al, 2001). A role for APC in mitosis might be critical for regulation of genomic stability and proper chromosome segregation.…”

Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia

“…These data must be considered preliminary, however, until it has been validated in vivo. Olmeda et al (2003) have proposed that b-catenin activation leads to a G2/M cell cycle arrest in the in vitro culture of keratinocyte cells. This appears at odds with the data presented herein.…”

AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer

“…16 b-catenin acts as an inducer of cell proliferation in different tumors. 23,24 Therefore, modulation of b-catenin levels can affect a multitude of cellular functions. For example, constitutive wnt signaling in malignant gastric adenocarcinoma shows higher levels of b-catenin in the nucleus.…”