Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1.
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 approximately -535 bp) and BS3 (-200 approximately -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.
Xie
Wei
W
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China Hefei, Anhui, 230027, China.
Jiang
Peng
P
Miao
Lin
L
Zhao
Ying
Y
Zhimin
Zhai
Z
Qing
Li
L
Zhu
Wei-guo
WG
Wu
Mian
M
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D050687:E2F1 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins