A Jekyll and Hyde Role of Cyclin E in the Genotoxic Stress Response: Switching from Cell Cycle Control to Apoptosis Regulation

Suparna Mazumder, Dragos Plesca and Alex Almasan

volume 6 | issue 12

15 June 2007
Pages: 1437 - 1442

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Cyclin E protein levels and associated kinase activity rise in late G1 phase, reach a peak at the G1/S transition, and quickly decline during S phase. The Cyclin E /Cdk2 complex has a well-established function in regulating two fundamental biological processes: cell cycle progression and DNA replication. However, Cyclin E expression is deregulated in a wide range of tumors. Our recent reports have uncovered a critical role for Cyclin E, independent of Cdk2, in the cell death of hematopoietic tumor cells exposed to genotoxic stress. An 18-kD C-terminal fragment of Cyclin E, p18-Cyclin E, which is generated by caspase-mediated cleavage in hematopoietic cells during genotoxic stress-induced apoptosis has a critical role in the amplification of the intrinsic apoptotic pathway. By interacting with Ku70, p18-Cyclin E liberates Bax, which participates in the amplification of apoptosis by sustaining a positive feedback loop targeting mitochondria. This process is independent of p53 function and new RNA or protein synthesis. Therefore, Cyclin E emerges as an arbiter of the genotoxic stress response by regulating a finite physiological balance between cell proliferation and death in hematopoietic cells.

Authors

Suparna Mazumder

The Lerner Research Institute; Cleveland, Ohio

Dragos Plesca

The Lerner Research Institute, Cleveland, Ohio

Alex Almasan