In silico modeling of phosphorylation dependent and independent c-Myc degradation

Abstract

Background: C-Myc plays an important role in cell proliferation, cell growth and in differentiation, making it a key regulator for carcinogenesis and pluripotency. Tight control of c-myc turnover is required by ubiquitin-mediated degradation. This is achieved in the system by two F-box proteins Skp2 and FBXW7. Results: Dynamic modelling technique was used to build two exclusive models for phosphorylation dependent degradation of Myc by FBXW7 (Model 1) and phosphorylation independent degradation by Skp2 (Model 2). Sensitivity analysis performed on these two models revealed that these models were corroborating experimental studies. It was also seen that Model 1 was more robust and perhaps more efficient in degrading c-Myc. These results questioned the existence of the two models in the system and to answer the question a combined model was hypothesised which had a decision making switch. The combined model had both Skp2 and FBXW7 mediated degradation where again the latter played a more important role. This model was able to achieve the lowest levels of ubiquitylated Myc and therefore functioned most efficiently in degradation of Myc. Conclusion: In this report, c-Myc degradation by two F-box proteins was mathematically evaluated based on the importance of c-Myc turnover. The study was performed in a homeostatic system and therefore, prompts the exploration of c-Myc degradation in cancer state and in pluripotent state.