title: HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2 (in silico discovery).
abstract: Stability of the 'guardian of the genome' tumor suppressor protein p53 is regulated predominantly through its ubiquitination. The ubiquitin-specific protease HAUSP plays an important role in this process. Recent experiments showed that p53 demonstrates a differential response to changes in HAUSP which nature and significance are not understood yet. Here a data-driven mathematical model of the Mdm2-mediated p53 ubiquitination network is presented which offers an explanation for the cause of such a response. The model predicts existence of the HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2. This switch suggests a potential role of HAUSP as a downstream target of stress signals in cells. The model accounts for a significant amount of experimental data, makes predictions for some rate constants, and can serve as a building block for the larger model describing a complex dynamic response of p53 to cellular stresses.
authors.affiliation: Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, United States. brazhnik@vt.edu
authors.forename: Paul
authors.initials: P
authors.lastname: Brazhnik
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Kohn
mesh_terms: D000818:Animals; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D008954:Models, Biological; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases