E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination.
Overexpression of c-Myc or E2F1 sensitizes host cells to various types of apoptosis. Here, we found that overexpressed c-Myc or E2F1 induces accumulation of reactive oxygen species (ROS) and thereby enhances serum-deprived apoptosis in NIH3T3 and Saos-2. During serum deprivation, MnSOD mRNA was induced by NF-kappaB in mock-transfected NIH3T3, while this induction was inhibited in NIH3T3 overexpressing c-Myc or E2F1. In these clones, E2F1 inhibited NF-kappaB activity by binding to its subunit p65 in competition with a heterodimeric partner p50. In addition to overexpressed E2F1, endogenous E2F1 released from Rb was also found to inhibit NF-kappaB activity in a cell cycle-dependent manner by using E2F1(+/+) and E2F1(-/-) murine embryonic fibroblasts. These results indicate that E2F1 promotes apoptosis by inhibiting NF-kappaB activity.
Tanaka
Hirokazu
H
Department of Hematology/Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Japan.
Matsumura
Itaru
I
Ezoe
Sachiko
S
Satoh
Yusuke
Y
Sakamaki
Toshiyuki
T
Albanese
Chris
C
Machii
Takashi
T
Pestell
Richard G
RG
Kanakura
Yuzuru
Y
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D018797:Cell Cycle Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D004247:DNA; D013482:Superoxide Dismutase