A role for 14-3-3 tau in E2F1 stabilization and DNA damage-induced apoptosis.
Genotoxic stress triggers apoptosis through multiple signaling pathways. Recent studies have demonstrated a specific induction of E2F1 accumulation and a role for E2F1 in apoptosis upon DNA damage. Induction of E2F1 is mediated by phosphorylation events that are dependent on DNA damage-responsive protein kinases, such as ATM. How ATM phosphorylation leads to E2F1 stabilization is unknown. We now show that 14-3-3 tau, a phosphoserine-binding protein, mediates E2F1 stabilization. 14-3-3 tau interacts with ATM-phosphorylated E2F1 during DNA damage and inhibits E2F1 ubiquitination. Depletion of 14-3-3 tau or E2F1, but not E2F2 or E2F3, blocks adriamycin-induced apoptosis. 14-3-3 tau is also required for expression and induction of E2F1 apoptotic targets, such as p73, Apaf-1, and caspases, during DNA damage. Together, these data demonstrate a novel function for 14-3-3 tau in the regulation of E2F1 protein stability and apoptosis during DNA damage.
Wang
Bing
B
Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Alabama 35294-3300, USA.
Liu
Kang
K
Lin
Fang-Tsyr
FT
Lin
Weei-Chin
WC
D048948:14-3-3 Proteins / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D004355:Drug Stability; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005982:Glutathione Transferase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C485192:green fluorescent protein, Aequorea victoria; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D005982:Glutathione Transferase; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases