Tumor suppressor protein p53 is negatively regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. We investigated interaction models consisting of p53, Mdm2 and MdmX. Our simulations show that MdmX could amplify and stabilize DNA damage-induced p53 responses. These effects of MdmX involve a reservoir-based mechanism with simple competitive interactions. The amplification effect of MdmX induced switch-like p53 responses early after DNA damage. Late in the DNA damage response, MdmX dampened oscillations, suggesting that MdmX could suppress p53 activity when p53 activity is subject to progressive rise due to the feedback between p53 and Mdm2.
Citation: PLOS Computational Biology
Pub Type: Journals
Cell networks, cell regulation, complex systems, metabolic and regulatory networks, network simulation, systems biology