Notch-Dependent Cell Cycle Arrest Is Associated With Downregulation of Minichromosome Maintenance Proteins

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Abstract
Perturbation of the Notch signaling pathway has been implicated in the pathogenesis of human cardiovascular diseases, and animal models have confirmed the requirement of Notch during cardiovascular development. We recently demonstrated that Notch activation delays S-phase entry and contributes to endothelial contact inhibition. Minichromosome maintenance (MCM) proteins, components of the prereplicative complex (pre-RC), are essential for DNA replication. Here, we report that Notch-mediated cell cycle arrest is associated with downregulation of MCM2 and MCM6 in endothelial cells and human fibroblasts. Downregulation of MCM proteins is also observed on activation of C promoter binding factor (CBF1) and is mediated by inhibition of Rb phosphorylation, as demonstrated using a constitutively active Rb mutant. Although the effects of the Notch pathway are cell-type specific and context-dependent, in cell types where Notch has an antiproliferative effect, downregulation of MCM proteins may be a common mechanism to inhibit DNA replication.