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E2F-1 Overexpression in U2OS Cells Increases Cyclin B1 Levels and cdc2 Kinase Activity and Sensitizes Cells to Antimitotic Agents

¹ The Cancer Institute of New Jersey, Robert Wood Johnson School of Medicine, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey; ² Joan and Sanford I. Weill Graduate School of Medical Sciences of Cornell University; and ³ Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Joseph R. Bertino, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08903. Phone: 732-235-8510; Fax: 732-235-8181; E-mail: bertinoj{at}umdnj.edu.

The E2F transcription factors play a critical role in coordinating transcription of specific genes essential for G₁-S transition. In early G₁, the retinoblastoma protein (pRB) becomes phosphorylated by cyclin-dependent kinases, disrupting pRB binding to E2F-1-3, allowing "free" E2F to regulate genes involved in proliferation. In the present study, we used a tetracycline E2F-1 inducible U2OS osteosarcoma cell line to investigate the effect of increasing levels of E2F-1 on the cytotoxicity of various chemotherapeutic drugs. Upon overexpression of E2F-1, there was no detectable change in cytotoxicity to doxorubicin, cisplatin, 5-fluorouracil, or etoposide. In contrast, overexpression of E2F-1 resulted in a marked increase in sensitivity to vinblastine and paclitaxel, drugs that are known to be more effective against cells in M phase. Therefore, we investigated the effect of E2F-1 overexpression on proteins regulating the G₂-M transition and M phase, in particular cyclin B1 and cdc2 kinase. Cyclin B1 mRNA and protein levels increased within 24 hours of E2F1 induction together with an increase in associated cdc2 kinase activity. Overexpression of cyclin B1 also resulted in a specific increase in sensitivity to paclitaxel and an increase in the cellular growth rate. Knockdown of cyclin B1 using an RNA interference oligo resulted in a slower cellular growth rate and an increase in resistance to paclitaxel. These studies add support to recent reports that show E2F regulates genes involved in mitotic entry and exit and allow the suggestion that mitotic inhibitors may have selective effects in tumors that overexpress E2F-1. (Cancer Res 2006; 66(14): 7253-60)

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