title: Qualitative network modeling of the Myc-p53 control system of cell proliferation and differentiation.
abstract: A kinetic model of a molecular control system for the cellular decision to proliferate or differentiate is formulated and analyzed for the purpose of understanding how the system can break down in cancer cells. The proposed core of this control system is composed of the transcription factors Myc and p53. The network of interactions between these factors involves negative and positive feedback loops that are linked to pathways involved in differentiation, cell cycle, and apoptosis. Understanding the dynamics of the Myc-p53 control system is aided by the postulate that there exists a cancer zone defined as a range of oncogenic Myc activities where the probability of initiating cancer is high. We propose that an essential role of p53 is to prevent the system from entering or staying too long in the cancer zone by downregulating Myc or, when Myc activity somehow becomes too high, by inducing apoptosis, cell cycle arrest, or differentiation. Kinetic modeling illustrates how deletions or aberrations in PTEN, MDM2, and ARF (genes implicated in various cancers, including glioma) affect the Myc-p53 control system. In addition, computer simulations demonstrate how this control system generates different cellular phenotypes characterized by rates of cellular differentiation and proliferation.
authors: Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. agudabd@mail.nih.gov
authors: Baltazar D
authors: BD
authors: Aguda
authors: Yangjin
authors: Y
authors: Kim
authors: Hong Sug
authors: HS
authors: Kim
authors: Avner
authors: A
authors: Friedman
authors: Howard A
authors: HA
authors: Fine
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D025461:Feedback, Physiological; D017353:Gene Deletion; D006801:Humans; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D051059:PTEN Phosphohydrolase; D020727:ADP-Ribosylation Factors