A Dual Role of Cyclin E in Cell Proliferation and Apotosis May Provide a Target for Cancer Therapy

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). 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.

cAMP induces autophagy via a novel pathway involving ERK, cyclin E and Beclin 1

“…In addition to its role in cell cycle progression, cyclin E has also been reported to play a role in regulating apoptosis in hematopoietic cells. [47][48][49] Moreover, we previously showed that cAMP-signaling in human ASCs uncoupled cyclin E from cell cycle progression and instead directed cyclin E to render ASCs sensitive to γ-irradiation-induced apoptosis in an ERKdependent manner. 16 We therefore explored the possibility that cyclin E also might be involved in cAMP-mediated induction of autophagy.…”

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

“…Even though not the objective of the present report, future studies will examine the effects of 7Me-IEITC on specific cell-cycle checkpoints in ovarian cancer cells. Targeting cell cycle checkpoints has been suggested as an alternative approach to anti-cancer therapies [51,52].…”

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

“…Unexpected evidence came from the experimental results of the same group, indicating that p18-cyclin E interacts with the Ku-70, a critical component in the non-homologous end-joining repair. It is speculated that interaction of cyclin E might inhibit the activity of Ku-70 and hence augments the apoptotic process by inhibiting the DNA repair mechanism (Mazumder et al, 2004).…”