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UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts

Oncogene volume 20, pages 6784–6793 (2001)Cite this article

A Corrigendum to this article was published on 11 December 2001

Abstract

We address here the effects of increasing fluencies of UV-radiation on stability, modifications, activity and HDM2-interactions of endogenous p53 tumor suppressor and on cellular damage response of human diploid fibroblasts. Low amounts of UVB/C-radiation induced a transient cell cycle arrest of the cells which correlated with rapid but transient increase in p53 levels. In contrast, high UV-fluency caused cell apoptosis and a slower but sustained increase in p53. Regulation of p53 target genes was highly dependent on the radiation dose used. Whereas low doses induced p21/Cip1/Waf1 and HDM2, high doses induced only GADD45 and BAX increasing the BAX:BCL-2 ratio. The levels of HDM2, a negative regulator of p53, increased only by the low dose of UVC and p53-HDM2 association was promoted. In the absence of HDM2-induction after the high dose of UV-radiation p53-HDM2-interaction was promoted, but HDM2 failed to downregulate p53. p53 site-specific modifications (Ser15, Ser33, Ser37, Lys382) varied kinetically and were dependent on the fluency of the radiation used. Maximal phosphorylation of p53 on Ser15 and Ser33 correlated with increased levels of HDM2-free p53. The results suggest that regulation of p53 and HDM2 by UV-radiation is highly dose-dependent and contributes to the outcome of the cellular response.

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Acknowledgements

Annamari Heiskanen is thanked for excellent technical assistance. We thank Leif Andersson for PARP antibody and Toivo Maimets for 2A10 antibody. This study was supported by the Academy of Finland, Centre of Excellence Program (grant no 44895), Biocentrum Helsinki, the Finnish Cancer Organization and the Ida Montin Foundation.

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Authors and Affiliations

  1. Department of Virology, Haartman Institute, University of Helsinki, PO Box 63, Helsinki, FIN-00014, Finland

    Leena Latonen & Marikki Laiho

  2. Biology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, 104-0045, Tokyo, Japan

    Yoichi Taya

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  1. Leena Latonen
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  2. Yoichi Taya
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Correspondence to Marikki Laiho.

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Latonen, L., Taya, Y. & Laiho, M. UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts. Oncogene 20, 6784–6793 (2001). https://doi.org/10.1038/sj.onc.1204883

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