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). Rb, as well as Cdc6, NPAT, and nucleophosmin, critical components of cell proliferation and DNA replication, respectively, are targets of Cyclin E/Cdk2 phosphorylation. There are a number of putative binding sites for E2F in the cyclin E promoter region, suggesting an E2F-dependent regulation. Skp2 and Fbw7 are novel proteins, responsible for ubiquitin-dependent proteolysis of Cyclin E. The tight regulation of cyclin E expression, both at the transcriptional level and by ubiquitin-mediated proteolysis, indicates that it has a major role in the control of the G1-and S-phase transitions. Cyclin E is also transcriptionally regulated during radiation-induced apoptosis of hematopoietic cells. In addition to its biological roles, deregulated cyclin E expression has an established role in tumorigenesis. Cell cycle regulatory molecules, such as cyclin E, are frequently deregulated in different types of cancers, where overexpressed native or low molecular weight forms of Cyclin E have a significant role in oncogenesis. During apoptosis of hematopoietic cells, caspasedependent proteolysis of Cyclin E generates a p18-Cyclin E variant. Understanding the role of Cyclin E in apoptosis may provide a novel target, which may be effective in cancer therapy. This review summarizes what is known about the biological role of cyclin E, its deregulation in cancer, and the opportunities it may provide as a target in clinical therapy.

The retinoblastoma (pRb), p107, and p130 pocket proteins bind to the E2F transcription factors to control gene expression. E2F4 protein levels increased and accumulated in the nuclei of prostate carcinoma cells subjected to ionizing radiation (IR). The IR-induced increase of E2F4 levels led to an increase in E2F4 binding to p130 but had no effect on E2F4/p107 or E2F5/p130 complexes. The increase in E2F4/p130 association after IR was observed in prostate carcinoma cells regardless of their sensitivity to androgens, but not in breast carcinoma cells. E2F4/p130 complex formation was dependent on dissociation of p130 from cyclindependent kinase 2 and p130 dephosphorylation. Disruption of E2F4 through small interfering RNA prevented p130/E2F4 complex formation and sensitized cells to IR-induced apoptosis, leading to caspase-3 activation, cleavage of its substrate, poly(ADP-ribose) polymerase, and nuclear condensation. The E2F4/p130 pocket protein complex emerges as a new target of radiation in prostate carcinoma cells.