p400 is required for E1A to promote apoptosis.
The adenovirus E1A oncoprotein promotes proliferation and transformation by binding cellular proteins, including members of the retinoblastoma protein family, the p300/CREB-binding protein transcriptional coactivators, and the p400-TRRAP chromatin-remodeling complex. E1A also promotes apoptosis, in part, by engaging the ARF-p53 tumor suppressor pathway. We show that E1A induces ARF and p53 and promotes apoptosis in normal fibroblasts by physically associating with the retinoblastoma protein and a p400-TRRAP complex and that its interaction with p300 is largely dispensable for these effects. We further show that E1A increases p400 expression and, conversely, that suppression of p400 using stable RNA interference reduces the levels of ARF, p53, and apoptosis in E1A-expressing cells. Therefore, whereas E1A inactivates the retinoblastoma protein, it requires p400 to efficiently promote cell death. These results identify p400 as a regulator of the ARF-p53 pathway and a component of the cellular machinery that couples proliferation to cell death.
Samuelson
Andrew V
AV
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Narita
Masako
M
Chan
Ho-Man
HM
Jin
Jianping
J
de Stanchina
Elisa
E
McCurrach
Mila E
ME
Narita
Masashi
M
Fuchs
Miriam
M
Livingston
David M
DM
Lowe
Scott W
SW
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D050881:E1A-Associated p300 Protein; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D004265:DNA Helicases; C498558:EP400 protein, human; D020727:ADP-Ribosylation Factors