Cyclin E induction by genotoxic stress leads to apoptosis of hematopoietic cells.
Cyclin E is essential for progression through the G1 phase of the cell cycle and initiation of DNA replication by interacting with, and activating its catalytic partner, the cyclin-dependent kinase 2 (Cdk2). We found a substantial increase in cyclin E mRNA, accompanied by increased production of cyclin E protein and cyclin E/Cdk2 kinase activity in multiple myeloma and lymphoma cells following irradiation. Cyclin E expression increased early in a time and dose-dependent manner, with a three-fold induction reached 8 h following gamma-irradiation. Run-on analyses indicated a predominantly transcriptional regulation of cyclin E. Stable overexpression of cyclin E, but not cyclin D1, sensitized IM-9 cells to gamma-irradiation-induced apoptosis; in contrast, a dominant-negative Cdk2, prevented apoptosis. Irradiation of cyclin E overexpressing cells led to an enhanced caspase activation and exposure of the phosphatidylserine on the plasma membrane, two key markers of apoptosis, events which were completely abolished in cells expressing a dominant-negative Cdk2. This study identifies cyclin E as a target for activation by ionizing radiation and which plays a functional role in apoptosis of hematopoietic cells. Oncogene (2000) 19, 2828 - 2835
Mazumder
S
S
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, OH 44195, USA.
Gong
B
B
Almasan
A
A
D017209:Apoptosis / Q000528:radiation effects*; D042846:CDC2-CDC28 Kinases; D002478:Cells, Cultured; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006801:Humans; D016399:Lymphoma, T-Cell / Q000473:pathology; D009101:Multiple Myeloma / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D019927:Cyclin E; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases