The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1.
Proper regulation of cell cycle progression is pivotal for maintaining genome stability. In a search for DNA damage-inducible, CHK1-modulated genes, we have identified BTG3 (B-cell translocation gene 3) as a direct p53 target. The p53 transcription factor binds to a consensus sequence located in intron 2 of the gene both in vitro and in vivo, and depletion of p53 by small interfering RNA (siRNA) abolishes DNA damage-induced expression of the gene. Furthermore, ablation of BTG3 by siRNA in cancer cells results in accelerated exit from the DNA damage-induced G2/M block. In vitro, BTG3 binds to and inhibits E2F1 through an N-terminal domain including the conserved box A. Deletion of the interaction domain in BTG3 abrogates not only its growth suppression activity, but also its repression on E2F1-mediated transactivation. We also present evidence that by disrupting the DNA binding activity of E2F1, BTG3 participates in the regulation of E2F1 target gene expression. Therefore, our studies have revealed a previously unidentified pathway through which the activity of E2F1 may be guarded by activated p53.
Ou
Yi-Hung
YH
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Chung
Pei-Han
PH
Hsu
Fu-Fei
FF
Sun
Te-Ping
TP
Chang
Wen-Ying
WY
Shieh
Sheau-Yann
SY
D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007438:Introns; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D011506:Proteins; D016159:Tumor Suppressor Protein p53
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