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Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function

Oncogene volume 20, pages 2559–2569 (2001)Cite this article

Abstract

Although retinoids are known to regulate gene transcription by activating retinoid receptors, the targets of retinoid receptors are largely unknown. This study indicates effective all-trans retinoic acid (RA)-induced differentiation of human embryonal carcinoma cells engages p53. Unexpectedly, RA has been found to activate the transactivation function of p53 in the human embryonal carcinoma cell line, NT2/D1, in a retinoid receptor-dependent manner. A derived RA-resistant line, NT2/D1-R1, is deficient in this activity and is co-resistant to cisplatin. This indicates that RA and cisplatin responses may share a common pathway involving p53 in embryonal carcinomas. RA has no effect on p53 steady-state protein levels in either line. RA enhances endogenous p53 transactivation activity in NT2/D1 but not NT2/D1-R1 cells. In addition, RA induces transactivation activity of a gal4-p53 fusion protein, suggesting that RA activates p53 independent of increasing p53 levels or sequence-specific DNA binding. This activity is absent in retinoic acid receptor γ (RARγ)-deficient NT2/D1-R1 cells but can be restored upon co-transfection with specific RARs. Transient transfection of a dominant-negative p53 construct in NT2/D1 cells blocks the RA-mediated transcriptional decline of a differentiation-sensitive reporter plasmid and enhances survival of NT2/D1 cells following cisplatin treatment. Taken together, these findings indicate that RA activates the intrinsic activation function of p53 by a novel mechanism independent of effects on p53 stability or DNA binding and that this activation may be a general mechanism that contributes to RA-mediated G1 arrest.

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Acknowledgements

We thank Dr Sarah Freemantle and Dr Sutisak Kitareewan for helpful discussion and Mr Jeffrey Chang for technical assistance. We thank Dr Nancy Rosenfield (Memorial Sloan Kettering Cancer Center) for providing DAOY cells. We thank Dr Moshe Oren (Weizmann Institute of Science), Dr Tucker Collins (Harvard Medical School), and Dr Bert Vogelstein (John Hopkins Medical School) for providing plasmid constructs. This work was supported by National Institute of Health R01-CA54494 (E Dmitrovsky) and R01-CA87546 (E Dmitrovsky) from the National Cancer Institute, and by the American Cancer Society grant RPG-90-019-10-DDC (E Dmitrovsky) and the National Cancer Institute Howard Temin Award K01-CA75154 (MJ Spinella) and from a grant from the Lance Armstrong Foundation (MJ Spinella). KH Dragnev was supported in part by the American Society of Clinical Oncology (ASCO) Young Investigator Award.

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  1. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, 03755, New Hampshire, NH, USA

    Joshua C Curtin, Konstantin H Dragnev, David Sekula, Allison J Christie, Ethan Dmitrovsky & Michael J Spinella

  2. Department of Medicine, Dartmouth Hitchcock-Medical Center, Lebanon, 03756, New Hampshire, NH, USA

    Konstantin H Dragnev & Ethan Dmitrovsky

  3. The Norris Cotton Cancer Center, Dartmouth Hitchcock-Medical Center, Lebanon, 03756, New Hampshire, NH, USA

    Konstantin H Dragnev, Ethan Dmitrovsky & Michael J Spinella

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Curtin, J., Dragnev, K., Sekula, D. et al. Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function. Oncogene 20, 2559–2569 (2001). https://doi.org/10.1038/sj.onc.1204370

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