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Proteasome-mediated degradation of Tob is pivotal for triggering UV-induced apoptosis

Oncogene volume 28, pages 401–411 (2009)Cite this article

Abstract

Eukaryotic cells respond to genotoxic stress by inducing cell growth arrest or apoptosis. Although the p53 tumor suppressor largely contributes to the response by regulating antiproliferative or pro-apoptotic genes, some genotoxic stresses including ultraviolet (UV) light induce apoptosis even in the absence of p53. The molecular mechanisms by which cells respond to UV in the p53-independent manner remain to be established. Here, we show that UV-induced stress promotes proteasome-dependent degradation of Tob, triggering an apoptotic signal. We found that Tob with either short deletion or a tag sequence at the C terminus was resistant to UV-induced degradation. Introduction of the degradation-resistant Tob impaired UV-induced apoptosis. Reciprocally, suppression of Tob by small interfering RNA (siRNA) resulted in frequent induction of apoptosis irrespective of the presence of functional p53 even at UV doses that do not promote Tob degradation. Finally, tob-deficient (tob−/−) mice and primary embryonic fibroblasts (MEFs) from tob−/− mice exhibit increased sensitivity to UV irradiation. Thus, proteasomal clearance of Tob provides a novel p53-independent pathway for UV-induced apoptosis.

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Acknowledgements

We thank Dr Seiji Takeuchi (University of Fukui, Japan) for technical advice about UV irradiation of animals, and Dr Robert Whittier (Institute of Medical Science, Tokyo, Japan) and Dr Marius Sudol (Weis Center for Research, Danville, PA, USA) for comments on the paper. We also thank members of our laboratory for scientific comments and valuable discussions. This study was supported by a grant for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan

    T Suzuki, J Tsuzuku, K Kawakami, T Miyasaka & T Yamamoto

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  1. T Suzuki
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  2. J Tsuzuku
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  3. K Kawakami
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  4. T Miyasaka
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Correspondence to T Yamamoto.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Suzuki, T., Tsuzuku, J., Kawakami, K. et al. Proteasome-mediated degradation of Tob is pivotal for triggering UV-induced apoptosis. Oncogene 28, 401–411 (2009). https://doi.org/10.1038/onc.2008.387

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