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Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity

Oncogene volume 24, pages 3853–3863 (2005)Cite this article

Abstract

The p53 protein is redox-sensitive in vitro but in vivo effectors of this sensitivity are not known. In yeasts deficient for thioredoxin (Trx) reductase (TRR), p53 accumulates in an inactive, oxidized form, suggesting a role for TRR-Trx in controlling p53. In mammalian cells, p53 binds to redox factor-1 (APE/Ref-1), an enzyme containing an abasic endonuclease domain involved in base excision repair, and a thiol reductase domain recycled by Trx and involved in regulating the transcription factor AP-1. To evaluate the role of TRR and APE/Ref-1 in p53 regulation, we have abrogated their expression using RNA interference in cell lines expressing wild-type p53. Inhibition of TRR resulted in accumulation of oxidized Trx and increased levels and DNA-binding activity of p53, with no phosphorylation of Ser15 or Ser20. In contrast, inhibition of APE/Ref-1 accelerated p53 protein turnover, resulting in a decrease in p53 levels and activity. However, inhibition of either TRR or APE/Ref-1 did not prevent activation and accumulation of p53 in response to DNA-damage by doxorubicin. When both factors were inhibited, basal levels of p53 were restored. These results suggest that TRR-Trx and APE/Ref-1 cooperate in the control of basal p53 activity, but not in its induction by DNA-damage.

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Abbreviations

ATM:

ataxia telangiectasia mutated

APE/Ref-1:

redox factor-1

BER:

base excision repair

Chk-2:

checkpoint kinase-2

DTT:

dithiothreitol

IR:

ionizing radiation

RNAi:

RNA interference

ROS:

reactive oxygen species

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

siRNA:

short inhibitory RNA

TRR:

thioredoxin reductase

Trx:

thioredoxin

UVA/UVB:

ultraviolet A (320–400 nm) or B (290–320 nm)

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Acknowledgements

The authors are grateful to Dr C Caron de Fromentel for critical reading, Dr K Mann for helpful discussions, to Dr A Puisieux and Dr M Oren for the gift of cell lines and to Mrs Hautefeuille for technical assistance. The support of the French Association against Cancer, of the French Ministry of National Education, Research and Technology, and of an IARC special training award to SS is acknowledged.

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  1. Group of Molecular Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372, Lyon, France

    Séverine Seemann & Pierre Hainaut

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Correspondence to Pierre Hainaut.

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Seemann, S., Hainaut, P. Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity. Oncogene 24, 3853–3863 (2005). https://doi.org/10.1038/sj.onc.1208549

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