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Phosphorylation of p53 on Thr55 by ERK2 is necessary for doxorubicin-induced p53 activation and cell death

Oncogene volume 23, pages 3580–3588 (2004)Cite this article

Abstract

We recently reported that exposure of human cervical carcinoma cells to doxorubicin results in extracellular signal-regulated kinase (ERK)2 activation, which in turn phosphorylates p53 on a previously uncharacterized site, Thr55. This study sought to clarify the biological significance of doxorubicin-induced Thr55 phosphorylation. In breast carcinoma MCF7 cells, doxorubicin (300 nM) activated ERK2 and induced phosphorylation of p53 on Thr55 residues. Pretreatment of MCF7 cells with an ERK2 chemical inhibitor, PD98059 or U0126, blocked doxorubicin-induced p53 activation and suppressed phosphorylation of p53Thr55. MCF55a cells were established by transfection of full-length p53 carrying Thr55 mutation (Thr to Ala) into MCF7 cells. Doxorubicin (500 nM) could not induce p53 activation in MCF55a cells, which showed significantly increased drug resistance toward doxorubicin. While the expression of the apoptotic protein, Bax, showed no difference between MCF7 and MCF55a cells, Bcl-2, an antiapoptotic protein, was constitutively expressed in MCF55a cells. The increase of Bcl-2 protein and/or Bcl-2/Bax ratio might at least partly contribute to the drug resistance of MCF55a cells. In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death.

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Acknowledgements

This research was supported by grant 89-FA01-1-4 from the Ministry of Education, Taiwan, ROC, and grant 91A1-CANT-1 from the National Health Research Institute, Taiwan, ROC to the Cancer Research Center, College of Medicine, National Taiwan University.

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Authors and Affiliations

  1. Department of Oncology, National Taiwan University Hospital, Taipei, 10016, ROC, Taiwan

    Pei Yen Yeh, Kun-Huei Yeh & Ann-Lii Cheng

  2. Cancer Research Center, College of Medicine, National Taiwan University, Taipei, ROC, Taiwan

    Pei Yen Yeh, Kun-Huei Yeh, Ying Chyi Song, Lucia Ling-Yuan Chang & Ann-Lii Cheng

  3. Division of Cancer Research, National Health Research Institutes, Taipei, ROC, Taiwan

    Shuang-En Chuang & Ann-Lii Cheng

  4. Department of Medical Research, Far Eastern Memorial Hospital, Taipei, ROC, Taiwan

    Kun-Huei Yeh

  5. Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan, South Road, Taipei, 10016, ROC, Taiwan

    Ann-Lii Cheng

  6. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, ROC, Taiwan

    Ann-Lii Cheng

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Correspondence to Ann-Lii Cheng.

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Yeh, P., Chuang, SE., Yeh, KH. et al. Phosphorylation of p53 on Thr55 by ERK2 is necessary for doxorubicin-induced p53 activation and cell death. Oncogene 23, 3580–3588 (2004). https://doi.org/10.1038/sj.onc.1207426

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