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 trans membrane proteins that signal through the Notch receptors. In many cases of human acute lymphoblastic T-cell leukemias, chromosomal translocations fus e a part of the Notch-1 gene to the T-cell receptor-beta locus (Ellison et at., 1991, Cell 66:649-661). The truncated Notch-1 allele encodes an aberra nt protein that lacks most of the extracellular domain and is constitutivel y activated (Pear et at., 1996, J Exp Med 183:2283-2291). A similarly trunc ated 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 27:6265-6273). The transformed cells grew to a high p opulation density in culture and were tumorigenic in vivo. It was unclear w hat roles Notch signaling played in neoplastic transformation. In this repo rt, we demonstrate that sustained activation of the Jagged2/Notch signal tr ansduction pathway induced continuous cell cycling in confluent rabbit-skin fibroblasts sensitive to density-dependent inhibition of cell division. Th e ability to overcome density-dependent inhibition of cell division correla ted with elevated cyclin-dependent kinase-2 (CDK2) activity and a lower lev el 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 constit utive activity was expressed. Taken together, our findings indicate that su stained activation of the Jagged2/Notch signal transduction pathway can ove rcome density-dependent inhibition of cell division and therefore may contr ibute to neoplastic transformation, J. Cell. Physiol. 185:425-431, 2000. (C ) 2000 Wiley-Liss, Inc.