- GA No. 23825
- Role: Principal Investigator
- Timeline: January 2020 – December 2024
- Funding: € 500 000,00
VHL syndrome (VHL) arises from pathogenic inactivation of the von Hippel-Lindau protein (pVHL). The pVHL mediates the degradation of HIF-1α transcription factor, thus regulating hypoxia response. In light of multiple types of cancer ascribed for VHL, different HIF-independent functions were attributed to pVHL. In particular it is thought to induce cell senescence, mediate assembly and regulation of the extracellular matrix (ECM), apoptosis as well as playing a role oxidative stress response. However, the biological role of these HIF-independent functions and their impact in cancer development is poorly understood. Preliminary results generated at the BiocomputingUp show that pVHL isoforms (pVHL30, pVHL19, pVHL172) form an articulated protein family which collectively regulate different cellular functions similarly to what already observed for both HIF and PHD protein families. The central hypothesis is that pVHLs exert different tissue-specific functions. Their selective alteration at the tissue level can be used to explain the vast inter- and intra-familiar phenotypes variability observed among VHL patients. This project aims at fulfilling multiple main goals, such as to fully characterize pVHL HIF-independent functions among different tissues, to generate highly integrated Petri-Net representations, to design a computational model of VHL-related cancer development, to characterize PHDs at the molecular level, to characterize the biological meaning of pVHL/CDKN1s interaction, to characterize the biological meaning of pVHL/MDM2 interaction. The project will provide a dynamic model of VHL-related cancers evolution. This will help diagnostic and prognostic screening of cancer patients. More broadly, the further expected results will unveil the biological meaning of pVHL HIF-independent functions and their role in cell cycle regulation. Collectively, these data will help to improve our knowledge to evaluate cancer risk in VHL patients.