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Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking

Oncogene volume 30, pages 4780–4790 (2011)Cite this article

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Abstract

Nuclear factor-κB (NF-κB) and insulin-like growth factor-1 (IGF-1)-mediated signaling is associated with different tumors including renal cell carcinoma. NF-κB- and IGF-1-mediated signaling is found to be inhibited in the presence of wild-type von Hippel–Lindau (VHL) tumor suppresser gene. Therefore, negative regulator of VHL may be a good target for regulating NF-κB and IGF-1R. In this study, we found that VHL, a tumor suppressor protein that downregulates the NF-κB activity and the stability of IGF-1R was depleted by TGase 2 through polymerization via crosslinking and proteasomal degradation in kidney, breast and ovary cancer cell lines. We also found that TGase 2 knockdown promotes hypoxia-inducible factor 1α (HIF-1α) degradation, and thereby decrease HIF-1α transcriptional activity. Importantly, VHL expression was decreased in vivo in TGase-2-transgenic mice, and this was associated with increased NF-κB activity and the levels of expression of IGF-1R, HIF-1α and erythropoietin in kidney tissue. These results suggest a novel mechanism of regulation of the VHL tumor suppressor by TGase 2 that appears to be independent of the known cancer regulatory mechanisms.

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Acknowledgements

This work was supported by a research grant (NCC0810180-1 and NCC1110011-1) from the National Cancer Center in Korea and by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (no. 20090086078).

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Authors and Affiliations

  1. Division of Cancer Biology, Cancer Cell and Molecular Biology Branch, Research Institute, Goyang, Korea

    D-S Kim, Y-B Choi, B-G Han, S-Y Park, D-H Kim, E-R Ahn, J-E Shin, B I Lee, K-M Hong & S-Y Kim

  2. Division of Cancer Biology, Cancer Resources Branch, Research Institute, Goyang, Korea

    Y Jeon & H Lee

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  1. D-S Kim
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Correspondence to S-Y Kim.

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Kim, DS., Choi, YB., Han, BG. et al. Cancer cells promote survival through depletion of the von Hippel–Lindau tumor suppressor by protein crosslinking. Oncogene 30, 4780–4790 (2011). https://doi.org/10.1038/onc.2011.183

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