E2F-1 as an anticancer drug target
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REVIEW
E2F-1 as an anticancer drug target Joseph R. Bertino • Debabrata Banerjee
Received: 1 October 2009 / Accepted: 5 October 2009 / Published online: 16 October 2009 Ó Springer-Verlag 2009
Abstract Mounting evidence indicates that the E2F transcription factors play an essential role in all aspects of cellular functions. Many human malignancies have been shown to overexpress one or more of the ‘‘activating’’ E2Fs. In some circumstances, down regulation as well as overexpression of E2F-1, leads to inhibition of cell growth. The emphasis in this review is placed on new data implicating microRNAs in the regulation of E2F activity and the efforts thus far to target this activity in order to cause tumor regression. Keywords E2F-1 Retinoblastoma protein Cancer MicroRNAs
Introduction In this review, we examine the rationale and effects of targeting one or more of the E2F family of transcription factors to inhibit tumor cell proliferation. Since the earlier reviews by Banerjee and Bertino [1] and Kaelin [2], knowledge of functions and regulation of the E2F family of proteins has expanded exponentially, and now includes reports of the interaction of certain microRNAs with E2F. To cover this expanding knowledge base would require a book length review. Our goal is to summarize and to J. R. Bertino is an American Cancer Society Professor. J. R. Bertino (&) D. Banerjee Departments of Medicine and Pharmacology, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry, 195 Little Albany Street, Room 3033, New Brunswick, NJ 08903, USA e-mail: [email protected]
critically review data that focuses on the therapeutic aspects of interdicting E2F function in cancer cells. For a more comprehensive review of the functions of the E2F family of transcription factors, see the reviews by DeGregori [3], Hallstrom and Nevins [4] and Polager and Ginsberg [5]. Anatomy and functions of The E2F family The retinoblastoma protein (Rb) controls E2F transcription factor function and deregulation of the components of this pathway is found in many human cancers [6–8]. During the G1 to S transition, Rb is sequentially phosphorylated by cyclin D/cdk4 or 6 complexes followed by cyclin E/cdk2, releasing binding of the ‘‘activating’’ E2Fs (E2F-1,2 and 3a) to Rb [9–11]. To date, eight members of the E2F family have been identified. Broadly, E2Fs-1–3, are generally considered to be transcriptional activators of genes, while E2Fs 4–6 are repressors of E2F gene function. Newly described members of the E2F family, E2F 7–8, lack activation domains, and have anti-proliferative functions. E2Fs exert their transcriptional activity as heterodimers, bound to DP 1–4. E2F-7 modulates the transcription of other E2F proteins, and does not require a DP binding partner [12–14]. Although the E2Fs are essential transcription factors for cell cycle progression, a large number of additional targets have been identified by microarray technology and recognition of E2F consensus binding sequences in promoters [15]. The E
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