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Drosophila von Hippel-Lindau tumor suppressor complex possesses E3 ubiquitin ligase activity
1Department of Viral Oncology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo, 170-8455, Japan. taso@jfcr.or.jp
Abstract:
Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene predispose individuals to a variety of human tumors, including renal cell carcinoma, hemangioblastoma of the central nervous system, and pheochromocytoma. Here we report on the identification and characterization of the Drosophila homolog of VHL. The predicted amino acid sequence of Drosophila VHL protein shows 29% identity and 44% similarity to that of human VHL protein. Biochemical studies have shown that Drosophila VHL protein binds to Elongins B and C directly, and via this Elongin BC complex, associates with Cul-2 and Rbx1. Like human VHL, Drosophila VHL complex containing Cul-2, Rbx1, Elongins B and C, exhibits E3 ubiquitin ligase activity. In addition, we provide evidence that hypoxia-inducible factor (HIF)-1alpha is the ubiquitination target of both human and Drosophila VHL complexes.
Insights
The von Hippel-Lindau (VHL) gene
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are linked to various human cancers, including renal cell carcinoma and pheochromocytoma.
- The VHL protein plays a critical role in cellular regulation and tumor suppression.
Purpose of the Study:
- To identify and characterize the Drosophila homolog of the VHL gene.
- To investigate the functional conservation of VHL protein in a model organism.
Main Methods:
- Bioinformatic analysis to identify the Drosophila VHL homolog.
- Biochemical assays to study protein interactions and enzymatic activity.
- Ubiquitination assays to identify protein targets.
Main Results:
- The Drosophila VHL protein shares significant sequence similarity with human VHL.
- Drosophila VHL forms a complex with Elongins B/C, Cul-2, and Rbx1, exhibiting E3 ubiquitin ligase activity.
- Hypoxia-inducible factor (HIF)-1alpha is identified as a ubiquitination target for both human and Drosophila VHL complexes.
Conclusions:
- The functional conservation of VHL and its associated complex in Drosophila provides a valuable model for studying VHL-related diseases.
- The findings highlight the conserved role of VHL in regulating hypoxia-inducible factors across species.