Abstract
E2F/DP transcription factors regulate cell proliferation and apoptosis. Here, we investigated the mechanism of the resistance of Drosophila dDP mutants to irradiation-induced apoptosis. Contrary to the prevailing view, this is not due to an inability to induce the apoptotic transcriptional program, because we show that this program is induced; rather, this is due to a mitochondrial dysfunction of dDP mutants. We attribute this defect to E2F/DP-dependent control of expression of mitochondria-associated genes. Genetic attenuation of several of these E2F/DP targets mimics the dDP mutant mitochondrial phenotype and protects against irradiation-induced apoptosis. Significantly, the role of E2F/DP in the regulation of mitochondrial function is conserved between flies and humans. Thus, our results uncover a role of E2F/DP in the regulation of mitochondrial function and demonstrate that this aspect of E2F regulation is critical for the normal induction of apoptosis in response to irradiation.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Apoptosis*
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Blotting, Western
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Cell Cycle
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Cell Proliferation
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Chromatin Immunoprecipitation
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DNA Damage / genetics
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DNA Damage / radiation effects
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / genetics
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Drosophila melanogaster / growth & development
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Drosophila melanogaster / metabolism*
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism*
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Fluorescent Antibody Technique
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Gamma Rays
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Humans
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Immunoenzyme Techniques
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Mitochondria / metabolism
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Mitochondria / pathology*
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Mitochondria / radiation effects
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology*
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Phenotype
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
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Tumor Cells, Cultured
Substances
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Dp transcription factor, Drosophila
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Drosophila Proteins
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E2F Transcription Factors
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E2f1 protein, Drosophila
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Trans-Activators
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Transcription Factors