Jagged2 induces cell cycling in confluent fibroblasts susceptible to density-dependent inhibition of cell division.

Jagged2 is a member of the DSL (Delta-Serrate-Lag-2) -ligand family of transmembrane proteins that signal through the Notch receptors. In many cases of human acute lymphoblastic T-cell leukemias, chromosomal translocations fuse a part of the Notch-1 gene to the T-cell receptor-beta locus (Ellison et al., 1991, Cell 66:649-661). The truncated Notch-1 allele encodes an aberrant protein that lacks most of the extracellular domain and is constitutively activated (Pear et al., 1996, J Exp Med 183:2283-2291). A similarly truncated version of Notch-1 was capable of transforming primary baby rat kidney cells in cooperation with the E1A oncogene of adenovirus (Capobianco et al., 1997, Mol Cell Bio 17:6265-6273). The transformed cells grew to a high population density in culture and were tumorigenic in vivo. It was unclear what roles Notch signaling played in neoplastic transformation. In this report, we demonstrate that sustained activation of the Jagged2/Notch signal transduction pathway induced continuous cell cycling in confluent rabbit-skin fibroblasts sensitive to density-dependent inhibition of cell division. The ability to overcome density-dependent inhibition of cell division correlated with elevated cyclin-dependent kinase-2 (CDK2) activity and a lower level of induction of the CDK inhibitor p27 in the target cells. Similar cell-cycle effect was seen when a truncated mouse Notch-1 construct with constitutive activity was expressed. Taken together, our findings indicate that sustained activation of the Jagged2/Notch signal transduction pathway can overcome density-dependent inhibition of cell division and therefore may contribute to neoplastic transformation.