Notch-dependent cell cycle arrest is associated with downregulation of minichromosome maintenance proteins.
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.
Department of Medical Biophysics, British Columbia Cancer Agency, Vancouver, Canada.
Michela
M
Noseda
Kyle
K
Niessen
Graeme
G
McLean
Linda
L
Chang
Aly
A
Karsan
D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D064111:Minichromosome Maintenance Complex Component 2; D064151:Minichromosome Maintenance Complex Component 6; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface / Q000502:physiology*; D051880:Receptors, Notch; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497761:NOTCH1 protein, human; C106075:NOTCH4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497570:RBPJ protein, human; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C084859:MCM2 protein, human; C103258:MCM6 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D064151:Minichromosome Maintenance Complex Component 6