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Cyclin E induction by genotoxic stress leads to apoptosis of hematopoietic cells

Oncogene volume 19, pages 2828–2835 (2000)Cite this article

Abstract

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 γ-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 γ-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.

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Acknowledgements

We would like to thank J Roberts (Fred Hutchinson Cancer Research Center), K Alevizopoulos and B Amati (Swiss Institute for Experimental Cancer Research, ISREC), A Gudkov and P Chumakov (University of Illinois at Chicago) for various constructs. We also thank Q Chen, G Chen, R Gronostajski and M Hitomi for critical reading of the manuscript and A Raber (Flow Cytometry Core facility) for help with flow cytometry; The FACS Vantage Cell Sorter was funded by the WM Keck Foundation. This work was supported in part by research grants from the US National Institutes of Health (RO1 CA82858 and CA81504).

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Authors and Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Suparna Mazumder, Bendi Gong & Alexandru Almasan

  2. Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Alexandru Almasan

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  1. Suparna Mazumder
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  2. Bendi Gong
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Mazumder, S., Gong, B. & Almasan, A. Cyclin E induction by genotoxic stress leads to apoptosis of hematopoietic cells. Oncogene 19, 2828–2835 (2000). https://doi.org/10.1038/sj.onc.1203623

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