E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression

Abstract

The p53 tumor suppressor protein is a transcription factor that exerts its effects on the cell cycle via regulation of gene expression. Although the mechanism of p53-dependent transcriptional activation has been well-studied, the molecular basis for p53-mediated repression has been elusive. The E2F family of transcription factors has been implicated in regulation of cell cycle-related genes, with E2F6, E2F7, and E2F8 playing key roles in repression. In response to cellular DNA damage, E2F7, but not E2F6 or E2F8, is up-regulated in a p53-dependent manner, with p53 being sufficient to increase expression of E2F7. Indeed, p53 occupies the promoter of the E2F7 gene after genotoxic stress, consistent with E2F7 being a novel p53 target. Ablation of E2F7 expression abrogates p53-dependent repression of a subset of its targets, including E2F1 and DHFR, in response to DNA damage. Furthermore, E2F7 occupancy of the E2F1 and DHFR promoters is detected, and expression of E2F7 is sufficient to inhibit cell proliferation. Taken together, these results show that p53-dependent transcriptional up-regulation of its target, E2F7, leads to repression of relevant gene expression. In turn, this E2F7-dependent mechanism contributes to p53-dependent cell cycle arrest in response to DNA damage.

Transcriptional and Translational Regulation of C/EBPβ-HDAC1 Protein Complexes Controls Different Levels of p53, SIRT1, and PGC1α Proteins at the Early and Late Stages of Liver Cancer

“…In this paper, we determined a pathway by which DENmediated liver cancer eliminates this pathway. Another target of p53 within the cell cycle is E2F7 (20). We found that CUGBP1-C/EBP␤-HDAC1-mediated repression of p53 also reduces levels of E2F7.…”

“…Therefore, it operates as a dominant negative molecule by binding to DNA and inhibiting activities of other members of E2F family, leading to inhibition of cell proliferation. It has been shown recently that p53 up-regulates transcription of E2F7 and that this activation contributes to p53-dependent growth arrest (20). Quantitative RT-PCR and Western blotting showed that both mRNA and protein levels of p21 and E2F7 are reduced at 10 and 30 weeks after DEN treatments (Fig.…”

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

“…The correct regulation of the E2F7 alternative exon is likely important for the cell, because use of the exon changes the reading frame and alters the C terminus of the protein, which is necessary for the transcriptional activation of its target genes. E2F7 has antiproliferative properties (61,62), and it is possible that SNORD27 changes observed in cancer influence E2F7-dependent cell cycle regulation.…”

Interaction of E2F7 Transcription Factor with E2F1 and C-terminal-binding Protein (CtBP) Provides a Mechanism for E2F7-dependent Transcription Repression

“…ChIP-sequencing analysis reveals that E2F7 binds to multiple G 1 /S-regulated genes and represses their transcription (16). E2F7 is induced by p53 and is involved in cell cycle arrest response to DNA damage and cellular senescence (17)(18)(19). Recent studies using mouse model systems also show that the atypical E2Fs are involved in angiogenesis, polyploidization, and placental development (20 -23).…”