Journal
EMBO JOURNAL
Volume 25, Issue 5, Pages 1046-1057Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7600999
Keywords
cancer; cell cycle; E2F; transcription; 14-3-3
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Funding
- MRC [G0500905, G9400953] Funding Source: UKRI
- Medical Research Council [G9400953, G0500905] Funding Source: researchfish
- Cancer Research UK [13058] Funding Source: Medline
- Medical Research Council [G0500905, G9400953] Funding Source: Medline
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The E2F family is composed of at least eight E2F and two DP subunits, which in cells exist as E2F/DP heterodimers that bind to and regulate E2F target genes. While DP-1 is an essential and widespread component of E2F, much less is known about the DP-3 subunit, which exists as a number of distinct protein isoforms that differ in several respects including the presence of a nuclear localisation signal (NLS). We show here that the NLS region of DP-3 harbours a binding site for 14-3-3 epsilon, and that binding of 14-3-3 epsilon alters the cell cycle and apoptotic properties of E2F. DP-3 responds to DNA damage, and the interaction between DP-3 and 14-3-3 epsilon is under DNA damage-responsive control. Further, 14-3-3 epsilon is present in the promoter region of certain E2F target genes, and reducing 14-3-3 epsilon levels induces apoptosis. These results identify a new level of control on E2F activity and, at a more general level, suggest that 14-3-3 proteins integrate E2F activity with the DNA damage response.
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