A jekyll and hyde role of cyclin E in the genotoxic stress response: switching from cell cycle control to apoptosis regulation.
Cyclin E protein levels and associated kinase activity rise in late G(1) phase, reach a peak at the G(1)/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.
Mazumder
Suparna
S
Department of Cancer Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Plesca
Dragos
D
Almasan
Alexandru
A
D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D040461:Gene Components; D019337:Hematologic Neoplasms / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D034961:Antigens, Nuclear; D019927:Cyclin E; D004268:DNA-Binding Proteins; D051028:bcl-2-Associated X Protein; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen