Notch1 promotes progression into the S phase of the cell cycle by inducing the expression of SKP2, a component of a ubiquitin ligase complex that degrades the CDK inhibitor p27kip1.

The Notch family of transmembrane receptors regulates both cell fate decisions and the maintenance of adult stem cells, processes that require precise control of the cell cycle. Although Notch1 activation had previously been shown to alter the cell cycle in hematopoietic progenitor cells and to delay their commitment to the myeloid lineage, a direct link between Notch1 and cell cycle control pathways had not been established in these cells.

Sarmento et al. now find the link and show that constitutive Notch1 activation drives cell cycling by increasing the activity of cyclin-dependent kinase-2 (CDK2), a protein that promotes progression into the S phase of the cell cycle. CDK2 activation resulted from the degradation of the CDK inhibitor protein p27^kip1, which was triggered by the Notch1-induced expression of a protein called SKP2—a component of a ubiquitin ligase complex that targets proteins for proteosomal degradation.

How Notch-induced changes in cell cycle kinetics influence differentiation programs is not completely clear. The authors suggest that a shortened G1 phase—during which cells are thought to be most responsive to fate-deciding differentiation signals—may minimize the window of differentiation opportunity and thus help maintain the progenitor cell pool.