Cyclin E induction by genotoxic stress leads to apoptosis of hematopoieticcells

Cyclin E is essential for progression through the G1 phase of the cell cycl e and initiation of DNA replication by interacting with, and activating its catalytic partner, the cyclin-dependent kinase 2 (Cdk2), We found a substa ntial increase in cyclin E mRNA, accompanied by increased production of cyc lin E protein and cyclin E/ Cdk2 kinase activity in multiple myeloma and ly mphoma cells following irradiation. Cyclin E expression increased early in a time and dose-dependent manner, with a threefold induction reached 8h fol lowing gamma-irradiation, Run-on analyses indicated a predominantly transcr iptional regulation of cyclin E, Stable overexpression of cyclin E, but not cyclin D1, sensitized IM-9 cells to gamma-irradiation-induced apoptosis; i n contrast, a dominant-negative Cdk2, prevented apoptosis. Irradiation of c yclin E overexpressing cells led to an enhanced caspase activation and expo sure of the phosphatidylserine on the plasma membrane, two key markers of a poptosis, events which were completely abolished in cells expressing a domi nant-negative Cdk2, This study identifies cyclin E as a target for activati on by ionizing radiation and which plays a functional role in apoptosis of hematopoietic cells. Oncogene (2000) 19, 2828-2835.