The plk1 Gene Regulatory Network Modeling Identifies Three Circuits for plk1-mediated Genomic Instability Leading to Neoplastic Transformation
Abstract
1. Introduction
2. Materials and Methods
2.1. Retrieving Genomic Instability-Associated Biological Processes Using PathwayStudio
2.2. Delimiting the Core of plk1- Associated Genomic Instability Events
2.3. Construction of the plk1 Core Genomic Instability Network
2.4. Mathematical Modeling and Generation of Relevant Simulation Scenarios
2.5. Transcriptomic Profiling and Survival Analysis
2.6. Cell Culture and Quantitative Real-Time Polymerase Chain Reaction
3. Results
3.1. Identifying and Integrating the Key Components of plk1-Mediated Genomic Instability Events in Cancer
3.2. Building the plk1 Core Genomic Instability Network
3.3. A Model for Genomic Instability Research
3.4. Simulation Scenarios Highlight a Synergy Between PLK1 and COHESIN Regulation
3.5. The Role of plk1 in Genomic Instability
3.5.1. First Circuit: Chromosomal Passenger Complex
3.5.2. Second Circuit: Mitotic Checkpoint Complex
3.5.3. Third Circuit: Anaphase/Cyclosome Promoter Complex
3.6. Circuit-Specific Deregulation and Prognostic Patterns in plk1-Driven Genomic Instability
3.7. Real Time PCR Analysis of Key Genes Predicted to Be Associated with Genome Instability Events
4. Discussion
4.1. Model Limitations and Assumptions
4.2. Deregulation Processes Leading to Genomic Instability
4.3. plk1: Oncogene and Tumor Suppressor
4.4. Model-Derived Hypotheses and Opportunities for Experimental Validation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
References
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Initial Concentration Value (µM) Per Simulation Scenario (Sce) | |||||
---|---|---|---|---|---|
Gene | IC | Sce1 | Sce2 | Sce3 | Sce4 |
cdk1 | 1.0 | 0.01 | 0.1 | 10 | 100 |
Gene | IC | Sce5 | Sce6 | Sce7 | Sce8 |
plk1 | 1.0 | 0.01 | 0.1 | 10 | 100 |
Gene | IC | Sce9 | Sce10 | Sce11 | Sce12 |
cohesin | 1.0 | 0.01 | 0.1 | 10 | 100 |
Gene | IC | Sce13 | Sce14 | Sce15 | Sce16 |
cdk1, plk1, cohesin | 1.0 | 0.01 | 0.1 | 10 | 100 |
Category | Biological Process | Biological Species | Biological Interactions |
---|---|---|---|
Diseases | FOXM1 Signaling in Prostate Cancer | 13 | 17 |
Cell processes | G2/M Phase Transition | 47 | 65 |
Cell processes | Metaphase/Anaphase Phase Transition | 15 | 22 |
Cell processes | Chromosome Condensation | 22 | 36 |
Pathological processes | DREAM Complex and FOXM1/MYBL2 Promote Cell Cycle Progression in Cancer | 36 | 56 |
Cell processes | Sister Chromatid Cohesion | 27 | 41 |
Cell processes | Spindle Assembly | 29 | 45 |
Cell processes | Kinetochore Assembly | 49 | 73 |
Cell processes | Cell Cycle Overview | 140 | 213 |
Total | 9 Biological processes | 378 | 568 |
Tool/Platform | Data Consolidation (Curated or Integrative Sources) | Network Representation | Simulation Environment | Scenario Building (e.g., PLK1 Overexpression, Knockout) | Relevance to PLK1 Regulation/Genomic Instability | Limitations |
---|---|---|---|---|---|---|
PLK1 Model (this work) | High—Manual curation of PLK1-specific regulation from primary literature and reviews | Mechanistic, reaction-based (SBGN) | Yes—ODE simulation in CellDesigner | Yes—Edits to concentrations, rates, logic | Focused on PLK1 in the context of genomic instability | Requires parameter estimation; limited to encoded components |
Reactome Pathway Browser | High—Expert-curated, literature-based | Mechanistic, biochemical steps | No—Static visualization only | Limited—Overlay gene expression or mutations | Contains mitotic roles of PLK1; curated context for mitosis | No dynamic behavior or causal testing |
Cytoscape + ReactomeFIViz | Medium—Uses imported pathways or user-generated data | Topological; interaction & influence networks | No native simulation | Partial—Node/edge manipulation, expression mapping | Visualizes PLK1’s neighborhood; combines pathway sources | Not mechanistic; lacks temporal modeling |
Pathway Commons | Very high—Aggregates >20 DBs (Reactome, Panther, HPRD) | Interaction-based (BioPAX format) | No—Data portal only | No—Requires export to SBML or Cytoscape | Useful for mining extended PLK1 network | Static; not simulation-ready without processing |
IPA (Ingenuity Pathway Analysis) | High—Curated and predicted interactions from multi-omics data | Causal and regulatory network inference | No—Statistical inference only | Limited—Predicts activation/inhibition based on input | Predicts PLK1 up/downstream effects from expression data | Proprietary; no kinetic or mechanistic modeling |
GSEA (Gene Set Enrichment Analysis) | None—Depends on user-defined gene sets | Not network-based; gene list comparison | No—Statistical enrichment tool | No—Identifies gene set activity in datasets | Can evaluate whether PLK1 targets or affected genes are enriched | No network structure or dynamic context |
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Suescum-Holguín, J.F.; Clavijo-Buriticá, D.C.; Carrillo-Borda, E.F.; Quimbaya, M.A. The plk1 Gene Regulatory Network Modeling Identifies Three Circuits for plk1-mediated Genomic Instability Leading to Neoplastic Transformation. Life 2025, 15, 799. https://doi.org/10.3390/life15050799
Suescum-Holguín JF, Clavijo-Buriticá DC, Carrillo-Borda EF, Quimbaya MA. The plk1 Gene Regulatory Network Modeling Identifies Three Circuits for plk1-mediated Genomic Instability Leading to Neoplastic Transformation. Life. 2025; 15(5):799. https://doi.org/10.3390/life15050799
Chicago/Turabian StyleSuescum-Holguín, Jeison F., Diana Carolina Clavijo-Buriticá, Edward Fabian Carrillo-Borda, and Mauricio Alberto Quimbaya. 2025. "The plk1 Gene Regulatory Network Modeling Identifies Three Circuits for plk1-mediated Genomic Instability Leading to Neoplastic Transformation" Life 15, no. 5: 799. https://doi.org/10.3390/life15050799
APA StyleSuescum-Holguín, J. F., Clavijo-Buriticá, D. C., Carrillo-Borda, E. F., & Quimbaya, M. A. (2025). The plk1 Gene Regulatory Network Modeling Identifies Three Circuits for plk1-mediated Genomic Instability Leading to Neoplastic Transformation. Life, 15(5), 799. https://doi.org/10.3390/life15050799