Published online 14 April 2006
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Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China Hefei, Anhui, 230027, China 1 Department of Biochemistry and Molecular Biology and the Cancer Research Center, Peking University Health Science Center 38 Xueyuan Road, Beijing, 100083, China 2 Central Laboratory, Anhui Provincial Hospital Hefei, Anhui, 230001, China
*To whom correspondence should be addressed. Tel: +86 551 3607324; Fax: +86 551 3606264; Email: wumian{at}ustc.edu.cn
Received January 10, 2006. Revised January 30, 2006. Accepted March 17, 2006.
Deregulated expression of E2F1 not only promotes S-phase entry but also induces apoptosis. Although it has been well documented that E2F1 is able to induce p53-dependent apoptosis via raising ARF activity, the mechanism by which E2F induces p53-independent apoptosis remains unclear. Here we report that E2F1 can directly bind to and activate the promoter of Smac/DIABLO, a mitochondrial proapoptotic gene, through the E2F1-binding sites BS2 (–542 
–535 bp) and BS3 (–200 –193 bp). BS2 and BS3 appear to be utilized in combination rather than singly by E2F1 in activation of Smac/DIABLO. Activation of BS2 and BS3 are E2F1-specific, since neither E2F2 nor E2F3 is able to activate BS2 or BS3. Using the H1299 ER-E2F1 cell line where E2F1 activity can be conditionally induced, E2F1 has been shown to upregulate the Smac/DIABLO expression at both mRNA and protein levels upon 4-hydroxytamoxifen treatment, resulting in an enhanced mitochondria-mediated apoptosis. Reversely, reducing the Smac/DIABLO expression by RNA interference significantly diminishes apoptosis induced by E2F1. These results may suggest a novel mechanism by which E2F1 promotes p53-independent apoptosis through directly regulating its downstream mitochondrial apoptosis-inducing factors, such as Smac/DIABLO.
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