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von Hippel–Lindau protein promotes Skp2 destabilization on DNA damage

Oncogene volume 30, pages 3127–3138 (2011)Cite this article

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Abstract

Germline mutations in the von Hippel–Lindau (VHL) tumor suppressor gene cause VHL disease, a rare and autosomal-dominant genetic syndrome. Because VHL protein (pVHL) is the master regulator of hypoxia-inducible factor alpha (HIFα), the most prominent feature of VHL disease is the deregulation of HIFα proteins. However, the precise mechanism by which the loss of pVHL function contributes to tumorigenesis is not fully understood. Here, we show that pVHL destabilizes the F-box protein Skp2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase. The β-domain of pVHL interacts with Skp2, stimulating proteasome-dependent Skp2 degradation, but the destabilization of Skp2 does not depend on the E3 ubiquitin ligase activity of pVHL. Notably, the generation of DNA damage induces Skp2 degradation, which is attenuated by the suppression of endogenous pVHL expression. One possible mechanism of pVHL-dependent Skp2 degradation entails the antagonizing of Akt-mediated Skp2 phosphorylation, which maintains Skp2 stability. Reintroduction of VHL into VHL-null renal cell carcinoma (RCC) cells decreased Skp2 levels and restored DNA damage-dependent Skp2 degradation. These results identify the tumor suppressor function of pVHL in delaying the S-phase progression to inhibit cell proliferation on DNA damage. Clinically, this report explains as to why Skp2 accumulates abnormally in RCC tissues.

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Abbreviations

BrdU:

bromodeoxyuridine

HIF:

hypoxia-inducible factor

RCC:

renal cell carcinoma

VHL:

von Hippel–Lindau

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Acknowledgements

This work was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare (0720460), the Korea Healthcare Technology R&D Project (A090281), and National Research Foundation Grant (NRF-2010-0018896) to H-DY, a grant from the Korea Healthcare R&D Project (A080181) to E-JC and by the Korea Student Aid Foundation (KOSAF) grant, funded by the Korea government (MEST) (S2-2008-000-00400-1) to JSR. We thank Dr B Bruene (Johann Wolfgang Goethe-University) and Dr DS Lim (KAIST) for invaluable materials.

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  1. Departments of Biomedical Sciences and Biochemistry and Molecular Biology, National Research Laboratory for Metabolic Checkpoint, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    J-S Roe, H-R Kim, I-Y Hwang & H-D Youn

  2. National Research Laboratory for Chromatin Dynamics, College of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

    E-J Cho

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Correspondence to H-D Youn.

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Roe, JS., Kim, HR., Hwang, IY. et al. von Hippel–Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene 30, 3127–3138 (2011). https://doi.org/10.1038/onc.2011.40

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