E2F1 regulates p53R2 gene expression in p53-deficient cells

Abstract

The p53R2 gene encoding a small subunit of the ribonucleotide reductase has been identified as a p53-inducible gene. Although this gene is discovered as a target for p53 family proteins, the mechanism underlying p53R2 induction by DNA damage in p53-defiencient cells remains to be elucidated. In this study, we demonstrate that transcription factor E2F1 regulates the p53R2 gene expression in p53-deficient cells. We found that p53R2 was a target for E2F1 in DNA damage response (DDR), because ectopic expression of E2F1 in HCT116-p53(-/-) cells resulted in the increase of p53R2 mRNA and protein expression, and silencing E2F1 diminished its basic expression. Combination of luciferase reporter assay with overexpression or knockdown of E2F1 revealed that E2F1 directly activates the p53R2 gene. Chromatin immunoprecipitation (ChIP) assay showed E2F1 directly bound to the site (TTTGGCGG) at position -684 to -677 of the promoter under E2F1 overexpression or adriamycin (ADR) exposure. Moreover, silencing p53R2 could enhance apoptotic cell death in both HCT116-p53(-/-) and HCT116-p53(+/+) compared to ADR exposure, indicating that p53R2 may protect cancer cell from ADR-induced apoptosis. Together, we have identified a new role of E2F1 in the regulation of p53R2 expression in DDR, and silencing p53R2 may sensitize cancer cells to ADR-induced apoptosis. Our data support the notion that p53R2 is a potential target for cancer therapy. The involvement of E2F1-dependent p53R2 activation in DDR will provide further insight into the induction of p53R2 in p53-deficient cells. These data also give us a deeper understanding of E2F1 role in DDR.

p53R2 overexpression in cervical cancer promotes AKT signaling and EMT, and is correlated with tumor progression, metastasis and poor prognosis

“…30 It was shown that silencing p53R2 expression sensitizes CRC cancer cells to undergo apoptotic cell death in the presence of DNA damage agent. 46 These findings indicate that targeting p53R2 could enhance the effectiveness of ionizing radiation or DNA-damaging chemotherapy. Interestingly, in some tumors, p53R2 nuclear localization is much stronger than the cytoplasmic localization (Fig.…”

RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

“…Data for the RRM2B interaction network was downloaded from the BioGRID database [72] (10/25/2018) and analyzed by Cytoscape v. 3.6.1 [73]. Several interactions were added manually based on literature findings (RRM2B-FOXO3 [34], RRM2B-P21 [32], RRM2B-TP73 [74], RRM2B-E2F1 [33], RRM2B-MEK2 [75]).…”

“…Since the expression of RRM2B, MYC and several other 8q-amplicon genes was increased, we next tested if the products of these genes within the 8q-amplicon interact with RRM2B. RRM2B is regulated by p53 and p21 [32] and transcriptional factors, such as, E2F1 [33]. E2F1 regulates RRM2B in the absence of p53, and FOXO3 [34].…”

Crosstalk between E2F1 and P53 transcription factors in doxorubicin-induced DNA damage: evidence for preventive/protective effects of silymarin

“…However, as most of the currently used chemotherapeutic agents do have severe toxic effects, which may cause limitations in their usage, it would be worthwhile to consider having therapeutic agents that simultaneously have improved efficacy and less toxicity. Doxorubicin [DOX, C27H29NO11, (7S,9S)‐7‐[(2R,4S,5S,6S)‐4‐amino‐5‐hydroxy‐6‐methyloxan‐2‐yl]oxy‐6,9,11‐trihydroxy‐9‐(2‐hydroxyacetyl)‐4‐methoxy‐8,10‐dihydro‐7H‐tetracene‐5,12‐dione], an anthracycline, has been recognized as one of the main chemotherapeutic agents, which is used for various cancer therapy including: colon, breast, lung cancers and also for acute leukaemia and lymphomas . DOX works by inhibiting the enzyme topoisomerase II that in turn results in stopping of DNA replication processes.…”

“…Doxorubicin [DOX, C27H29NO11, (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione], an anthracycline, has been recognized as one of the main chemotherapeutic agents, which is used for various cancer therapy including: colon, breast, lung cancers and also for acute leukaemia and lymphomas. [3] DOX works by inhibiting the enzyme topoisomerase II that in turn results in stopping of DNA replication processes. Generation of free radicals that induces DNA and cell membrane damages is another mechanism of action for DOX chemotherapeutic effects.…”