Design and analysis of a Petri net model of the Von Hippel-Lindau (VHL) tumor suppressor interaction network

Giovanni Minervini; Elisabetta Panizzoni; Manuel Giollo; Alessandro Masiero; Carlo Ferrari; Silvio C E Tosatto

doi:10.1371/journal.pone.0096986

Design and analysis of a Petri net model of the Von Hippel-Lindau (VHL) tumor suppressor interaction network

PLoS One. 2014 Jun 2;9(6):e96986. doi: 10.1371/journal.pone.0096986. eCollection 2014.

Authors

Giovanni Minervini¹, Elisabetta Panizzoni¹, Manuel Giollo², Alessandro Masiero¹, Carlo Ferrari³, Silvio C E Tosatto¹

Affiliations

¹ Dept. of Biomedical Sciences, University of Padua, Padua, Italy.
² Dept. of Biomedical Sciences, University of Padua, Padua, Italy; Dept. of Information Engineering, University of Padua, Padua, Italy.
³ Dept. of Information Engineering, University of Padua, Padua, Italy.

Abstract

Von Hippel-Lindau (VHL) syndrome is a hereditary condition predisposing to the development of different cancer forms, related to germline inactivation of the homonymous tumor suppressor pVHL. The best characterized function of pVHL is the ubiquitination dependent degradation of Hypoxia Inducible Factor (HIF) via the proteasome. It is also involved in several cellular pathways acting as a molecular hub and interacting with more than 200 different proteins. Molecular details of pVHL plasticity remain in large part unknown. Here, we present a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Algorithms*
Cluster Analysis
Computer Simulation
Gene Knockout Techniques
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Models, Biological*
Protein Interaction Maps*
Transcription, Genetic
Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

Hypoxia-Inducible Factor 1, alpha Subunit
Von Hippel-Lindau Tumor Suppressor Protein

Grants and funding

This work was supported by Associazione Italiana per la Ricerca sul Cancro(AIRC) Grant MFAG 12740 to ST. GM is an AIRC research fellow (http://www.airc.it/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.