p19ARF targets certain E2F species for degradation.
p19ARF suppresses the growth of cells lacking p53 through an unknown mechanism. p19ARF was found to complex with transcription factors E2F1, -2, and -3. Levels of endogenous or ectopically expressed E2F1, -2, and -3, but not E2F6, were reduced after synthesis of p19ARF, through a mechanism involving increased turnover. p19ARF-induced degradation of E2F1 depended on a functional proteasome, and E2F1 was relocalized to nucleoli when coexpressed with p19ARF. Consistent with reduced levels of E2F1 and E2F3, the proliferation of cells defective for p53 function was suppressed by p19ARF, and the effect was partially reversed by ectopic overexpression of E2F1. These results suggest a broader role for p19ARF as a tumor suppressor, in which targeting of certain E2F species may cooperate with stimulation of the p53 pathway to counteract oncogenic growth signals.
Department of Cancer Biology and Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
F
F
Martelli
T
T
Hamilton
D P
DP
Silver
N E
NE
Sharpless
N
N
Bardeesy
M
M
Rokas
R A
RA
DePinho
D M
DM
Livingston
S R
SR
Grossman
D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D050701:E2F6 Transcription Factor; D006801:Humans; D006868:Hydrolysis; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050699:E2F3 Transcription Factor; D050701:E2F6 Transcription Factor; D011506:Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53