ArticleOncogene2011
von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage.
Article in Oncogene, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Effect of ubiquitin protease system on DNA damage response in prostate cancer (Review).Experimental and therapeutic medicine · 2024Review
- ZNF292 suppresses proliferation of ESCC cells through ZNF292/SKP2/P27 signaling axis.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2021Article
- Metastatic Renal Cell Cancer-Systemic Therapy.Indian journal of surgical oncology · 2018Article
- Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity inOncotarget · 2018Article
- Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors.Scientific reports · 2017Article
- USP9X destabilizes pVHL and promotes cell proliferation.Oncotarget · 2016Article
- VHLdb: A database of von Hippel-Lindau protein interactors and mutations.Scientific reports · 2016Article
- The role of DNA damage and repair in decitabine-mediated apoptosis in multiple myeloma.Oncotarget · 2014Article
- Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2.Cell death & disease · 2013Article
- Phosphorylation and ubiquitination-dependent degradation of CABIN1 releases p53 for transactivation upon genotoxic stress.Nucleic acids research · 2013Article
- Von Hippel-Lindau disease (VHL): a need for a murine model with retinal hemangioblastoma.Histology and histopathology · 2012Review
- pVHL-mediated transcriptional repression of c-Myc by recruitment of histone deacetylases.Molecules and cells · 2012Article
- Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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