Abstract
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 14-3-3epsilon, and that binding of 14-3-3epsilon alters the cell cycle and apoptotic properties of E2F. DP-3 responds to DNA damage, and the interaction between DP-3 and 14-3-3epsilon is under DNA damage-responsive control. Further, 14-3-3epsilon is present in the promoter region of certain E2F target genes, and reducing 14-3-3epsilon 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / genetics
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14-3-3 Proteins / metabolism*
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Amino Acid Sequence
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Animals
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Apoptosis
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Apoptotic Protease-Activating Factor 1
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COS Cells
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Cell Cycle
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Chlorocebus aethiops
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DNA Damage*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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E2F1 Transcription Factor / genetics
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E2F1 Transcription Factor / metabolism
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E2F5 Transcription Factor / genetics
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E2F5 Transcription Factor / metabolism*
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Genes, Tumor Suppressor
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Molecular Sequence Data
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Mutation / genetics
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Nuclear Localization Signals
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic
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Proteins / genetics
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Proteins / metabolism
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Sequence Homology, Amino Acid
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Protein p73
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Tumor Suppressor Proteins
Substances
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14-3-3 Proteins
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APAF1 protein, human
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Apoptotic Protease-Activating Factor 1
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DNA-Binding Proteins
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E2F1 Transcription Factor
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E2F5 Transcription Factor
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Intracellular Signaling Peptides and Proteins
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Nuclear Localization Signals
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Nuclear Proteins
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Proteins
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Proteins