title: Cancer cell(s) cycle sequencing reveals universal mechanisms of apoptosis.
abstract: In this paper, cell cycle in higher eukaryotes and their molecular networks signals both in G1/S and G2/M transitions are replicated in silico. Biochemical kinetics, converted into a set of differential equations, and system control theory are employed to design multi-nested digital layers to simulate protein-to-protein activation and inhibition for cell cycle dynamics in the presence of damaged genomes. Sequencing and controlling the digital process of four micro-scale species networks (p53/Mdm2/DNA damage, p21mRNA/cyclin-CDK complex, CDK/CDC25/weel/SKP2/APC/CKI and apoptosis target genes system) not only allows the comprehension of the mechanisms of these molecule interactions but paves the way for unraveling the participants and their by-products, until now quite unclear, which have the task of carrying out (or not) cell death. Whatever the running simulations (e.g., different species signals, mutant cells and different DNA damage levels), the results of the proposed cell digital multi-layers give reason to believe in the existence of a universal apoptotic mechanism. As a consequence, we identified and selected cell check points, sizers, timers and specific target genes dynamic both for influencing mitotic process and avoiding cancer proliferation as much as for leading the cancer cell(s) to collapse into a steady stable apoptosis phase.
authors.affiliation: Department of Structural, Aerospace Engineering and Geotechnics, University of Palermo, Viale delle Scienze, Block 8, 90128, Palermo, Italy. romario@unipa.it
authors.forename: R M Ardito
authors.initials: RM
authors.lastname: Marretta
authors.forename: F
authors.initials: F
authors.lastname: Ales
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology*; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2