The VHL/HIF-axis in the regulation of cellular stress resistance

• Applicant: Professor Dr. Roman-Ulrich Müller
• Subject Area: Nephrology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249562722

Germline inactivation of the von Hippel-Lindau gene (VHL) causes the hereditary cancer syndrome von Hippel-Lindau disease, which predisposes affected individuals to the formation of malignant and benign tumors in several organs. In addition to this syndrome mutations in VHL are found in more than 80% of all cases of sporadic renal cell carcinoma making pVHL the most prominent renal tumor suppressor protein. As part of an E3 ubiquitin ligase complex, Von-Hippel-Lindau protein (pVHL) regulates the cellular response to hypoxia by mediating the proteasomal degradation of the hypoxia inducible factor HIF-1alpha. Surprisingly, we and others could recently demonstrate that genetic ablation of vhl-1, the Caenorhabditis elegans homolog of the mammalian VHL gene, induces longevity in the nematode. Changes in nematode lifespan are not only one of the best established model systems in aging research. Yet more importantly they reflect increased resistance to a row of stressors. In the case of pVHL the underlying molecular mechanisms have largely remained elusive. However the existing data allows to hypothesize the existence of a cellular balance between effective tumor suppression on the one hand and the response to cellular damage and regeneration on the other hand, which is regulated at least partly through activation of hypoxia-inducible factor signaling. In the framework of this project we are going to examine this hypothesis. Doing so we will clarify interaction with the MAP kinase signaling pathway. Furthermore both cell- and tissue-specific functions of pVHL in the regulation of stress resistance and paracrine non-cell autonomous effects of the VHL/HIF-axis will be analysed. We have already employed C. elegans as a model for studying cellular mechanisms of pathogenesis regarding renal disease successfully in the past. Accordingly clarifying the basic mechanisms of cellular stress resistance in this model organism will help understanding the renal response to stress in the context of acute kidney injury. Interestingly, several clinical trials are now evaluating the potential of interventions that increase C. elegans lifespan - such as ischemic pre-conditioning and caloric restriction - to reach improved organoprotection in the context of surgery or organotoxic pharmacological therapies. Shedding light on the molecular pathways involved in vhl-1 dependent regulation of lifespan and cellular stress resistance will be the overarching goal of this project. C. elegans is the perfect model organism to examine the underlying molecular mechanisms and to discover novel protective principles. Enhanced knowledge of these mechanisms will further strengthen the link between pVHL, cellular stress resistance, aging and tumorigenesis and contribute to the search for possible novel therapeutic targets e.g. in treatment and prevention of acute kidney injury.

• DFG Programme: Research Grants
• International Connection: USA
• Participating Persons: Professor Dr. Adam Antebi; Professor Dr. Thomas Benzing; Professor Dr. Martin Chalfie; Professor Dr. Thorsten Hoppe