Plk1 gene regulatory network involved in genomic instability
Description
Recently, the dynamics behind the events of genomic instability have gained relevance due to their association with specific genes and cellular mechanisms, which are presented as new and powerful therapeutic alternatives for the disease. Previous studies found the gene Plk1 as a candidate for genomic instability; however, the mechanisms by which the gene and its dysregulation could induce genomic instability events weren’t entirely clear. Therefore, to elucidate the mechanisms, gene circuits, and proteins involved in the genomic instability events promoted by Plk1, a novel approach that involved the reconstruction and modeling of the regulatory network of Plk1 was adopted. The network contains nine processes where Plk1 participates that are involved in maintaining the stability of the genome. Subsequently, mathematical modeling of the regulation network was carried out under a mass action law kinetic approximation to generate a model with 1030 reactions and 716 biological species. The simulations allowed the identification of three interaction circuits between proteins that can potentially induce a genomic instability event as a product of Plk1 dysregulation. Additionally, eight proteins previously associated with genomic instability were identified within the circuits and proposed to amplify the genome instability event. As a novelty, the proteins KIF2C and INCENP are postulated as candidates to participate in the genomic instability process. The information contained herein can be used to feed future models, which are built under similar approaches.
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Steps to reproduce
We used Pathway Studio (now EMBIO), an ELSEVIER tool, to collect relevant information linking the plk1 gene to biological processes commonly associated with genomic instability. The collected information, expressed as protein-protein interactions were manually curated and integrated into a gene regulatory network using CellDesigner software. Based on the regulatory network, a deterministic mathematical model was generated using elementary kinetics under the law of mass action. The parameters associated with each of the reactions present in the model were searched in the literature and estimated based on similarities between reactions due to the scarcity of these parameters. Finally, the simulations were performed ensuring a basal expression of all the proteins present in the model. It was also determined at what time interval the system reached a steady state and this time interval was used as a reference for the following simulations. Using the "plk1 gene regulatory network involved in genomic instability" model, different scenarios (unpublished data) were generated to answer the research question, where the concentration of core proteins was slightly and drastically changed in order to identify relevant molecular mechanisms, proteins, and genetic circuits to explain the involvement of Plk1 in genomic instability.