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Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-β-activated kinase 1

Oncogene volume 26, pages 3521–3531 (2007)Cite this article

Abstract

Molecular therapeutics is a recognized promising approach for melanoma, but relevant target genes remain elusive. We report that overload of the recently cloned H11/HspB8 induces apoptosis in 55% of examined melanoma cultures. Apoptosis was determined by activation of caspases-9 and -3 and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and was not seen in normal melanocytes. It was associated with H11/HspB8 complexation with transforming growth factor-β-activated kinase (TAK) 1 and activation of TAK1 and p38 mitogen activated protein 3 kinases. TAK1 was not bound, nor activated by the H11/HspB8 mutant W51C, which has dominant antiapoptotic activity. β-Catenin was phosphorylated by activated TAK1, inhibiting its nuclear accumulation and mictophthalmia-associated transcription factor and cyclin dependent kinase 2 expression. The dominant-negative TAK1 mutant K63W inhibited β-catenin phosphorylation and caspase activation. The data indicate that H11/HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation and suggest that H11/HspB8 is a promising molecular therapy target.

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Acknowledgements

Supported in part by grant AR42647 from NIAMD, NIH. BL, JML and MDG were supported by grant ES07263 from NIEHS, NIH.

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Author notes

  1. L Liu

    Present address: Department of Dermatology, The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan Province, 650032, PR China

  2. B Li and C C Smith: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA

    B Li, C C Smith, J M Laing, M D Gober, L Liu & L Aurelian

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  1. B Li
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  2. C C Smith
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  3. J M Laing
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  4. M D Gober
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Correspondence to L Aurelian.

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

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Li, B., Smith, C., Laing, J. et al. Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-β-activated kinase 1. Oncogene 26, 3521–3531 (2007). https://doi.org/10.1038/sj.onc.1210145

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