The regulation of stem cell self-renewal must balance the regenerative needs of tissues that persist throughout life with the potential for cell overgrowth, transformation and cancer. Here, we attempt to deconstruct the relationship that exists between cell-cycle progression and the self-renewal versus commitment cell-fate decision in embryonic and adult stem cells. Recent genetic studies in mice have provided insights into the regulation of the cell cycle in stem cells, including its potential modulation by the stem cell niche. Although the dynamics of the embryonic and adult stem cell cycles are profoundly dissimilar, we suggest that shared principles underlie the governance of this important decision point in diverse stem cell types.

Several lines of evidence suggest that accumulation of cytoplasmic ␤-catenin transduces an oncogenic signal. We show that ␤-catenin is ubiquitinated and degraded by the proteosome and that ␤-catenin stability is regulated by a diacylglycerol-independent protein kinase Clike kinase activity, which is required for ␤-catenin ubiquitination. We also define a six-amino acid sequence found in both ␤-catenin and the NF-B regulatory protein IB␣, which, upon phosphorylation, targets both proteins for ubiquitination. Mutation of a single serine within the ubiquitination targeting sequence prevents ubiquitination of ␤-catenin. Mutations within the ubiquitination targeting sequence of ␤-catenin may be oncogenic.

The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.