Model predictions of MDM2 mediated cell regulation.
In this work we present a mathematical approach to elucidate possible mechanisms involving mdm2 in the regulation of the cell cycle. It has been experimentally shown that the over-expression of MDM2 leads to decoupling of DNA synthesis with mitosis resulting in polyploidy cells with multiple copies of their genomes. The function of MDM2 that uncouples the DNA synthesis phase (S) and the Mitosis phase (M) is unclear. To answer this question, we first formulate a mathematical model of the dynamics of the cell cycle regulatory proteins during the DNA synthesis phase and mitosis. This model is then tested for bifurcation that produces period doubling cascades that we relate to the biological event of polyploidy. The model formulation, the underlying biology, and the bifurcation results to delineate the unknown function of MDM2 are presented. Based on reproducing known experimental result of polyploidy in MDM2 overexpressed cells, we propose several possible functions of mdm2, i.e., possible interactions with the other cell cycle regulating proteins that will result in uncoupling the S and M phases. We conclude that the most likely unknown function of MDM2 leading to the decoupling of the S and M phases is an obstruction of the activation of Cdc25C by MDM2.
Obeyesekere
Mandri N
MN
Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston 77030, USA. mobeyese@mdanderson.org
Tecarro
Edwin
E
Lozano
Guillermina
G
D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D008433:Mathematics; D008962:Models, Theoretical; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011003:Ploidies; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D020687:cdc25 Phosphatases / Q000378:metabolism
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D020687:cdc25 Phosphatases