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Depletion of the receptor for advanced glycation end products (RAGE) sensitizes towards apoptosis via p53 and p73 posttranslational regulation

Oncogene volume 32, pages 1460–1468 (2013)Cite this article

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Abstract

The receptor for advanced glycation endproduct (RAGE) is involved in diabetic complications and chronic inflammation, conditions known to affect the sensitivity towards apoptosis. Here, we studied the effect of genetically depleting RAGE on the susceptibility towards apoptosis. In murine osteoblastic cells, RAGE knockout increased both spontaneous and induced apoptosis. Decreased levels of B-cell lymphoma 2 protein and increased intrinsic apoptosis were observed in Rage−/− cells. Furthermore, loss of RAGE increased expression of the death receptor CD95 (Fas, Apo-1), CD95-dependent caspase activation and extrinsic apoptosis, whereas NF-kB-p65 nuclear translocation was diminished. Importantly, depletion of RAGE reduced the ubiquitination and degradation of p53 and p73 and increased their nuclear translocation. The increase of p53 and p73 transactivational activity was essential for the RAGE-dependent regulation of apoptosis, because knockdown of p53 and p73 significantly decreased apoptosis in RAGE-deficient but not in RAGE-expressing cells. Thus, the RAGE-mediated posttranslational regulation of p53 and p73 orchestrates a sequence of events culminating in control of intrinsic and extrinsic apoptosis signaling pathways.

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Acknowledgements

We thank Dr Subrata Biswas for isolation of MOC, Thomas Fleming for assistance with chromatin immunoprecipitation and electroporation, Dr Andreas Koch for assistance with flow cytometry, as well as Katja Lorenz and Petra Hill for expert technical assistance. This work was supported by a grant of the Dietmar Hopp Stiftung ‘Altern—Mobilität erhalten, Regeneration ermöglichen’ to MB, PN, AB and TS, by a grant of the Deutsche Forschungsgemeinschaft SFB938 to AB and by the grant of the Deutsche Forschungsgemeinschaft, Transregional Collaborative Research Centre SFB/TRR77, the Tumorzentrum Heidelberg/Mannheim and the Helmholtz Alliance on Immunotherapy of Cancer funded by the Initiative and Networking Fund of the Helmholtz Association to MM.

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  1. T Schilling and P P Nawroth: These authors share last authorship.

Authors and Affiliations

  1. Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany

    M Brune, A Bierhaus, T Schilling & P P Nawroth

  2. Department of Internal Medicine IV, University of Heidelberg, Heidelberg, Germany

    M Müller

  3. Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

    M Müller

  4. The MRC Toxicology Unit, Leicester, UK

    G Melino

  5. Department of Experimental Medicine and Biochemical Sciences, Biochemistry Laboratory, IDI-IRCCS, University of Rome, Rome, Italy

    G Melino

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Correspondence to M Brune.

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Brune, M., Müller, M., Melino, G. et al. Depletion of the receptor for advanced glycation end products (RAGE) sensitizes towards apoptosis via p53 and p73 posttranslational regulation. Oncogene 32, 1460–1468 (2013). https://doi.org/10.1038/onc.2012.150

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