title: On p21 tracking property in cancer cell unravelled bio-digitally in silico. Are apoptosis principles universal?
abstract: Upon severe DNA damage, p21 acts in a dual mode; on the one hand, it inhibits the cyclin-CDK complex for arresting the G2/M transition and on the other hand, it indirectly becomes an apoptotic factor by activating--in sequence--the retinoblastoma protein, E2F1 and APAF1 expressions. But, in a cancer cells proliferation, the mechanisms of, and participants in, the apoptosis failure remain unclear. Since the p21/p53/Mdm2 proteins network normally involves a digital response in a cancer cell, through an original design of a cell signalling-protein simulator, we demonstrate, in silico, that apoptosis phase instability is fully reciprocated by p21 mRNA irregular dynamics which operates according to a "tracking memory" principle. We show p21mRNA paradoxically ceases to act in concert with specific target genes and becomes an underlying accomplice of cancer proliferation. Here, we also identify the mechanisms for allowing the cancer cell to re-enter inside 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: G
authors.initials: G
authors.lastname: Barbaraci
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology; D003198:Computer Simulation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2