Multi-scale modeling identifies the role of p53-Gys2 negative feedback loop in cellular homeostasis

The transcription factor p53 is a tumor suppressor and strictly controlled p53 protein abundance coordinates cellular outcomes in response to various stresses. The glycogen synthase 2 (Gys2) and p53 generates a novel negative feedback circuit in which p53 represses Gys2 expression whereas Gys2 can stabilize p53 by competitive binding with MDM2. However, the dynamic role of p53-Gys2 negative feedback is still elusive. In current work, we recapitulated the main experimental findings using multi-scale modeling and emphasized the pivotal role of p53-Gys2 negative feedback loop to main cellular homeostasis. The multi-scale modeling strategy was used to simulate both in vitro and in vivo experimental findings. We found that expression of a key oncoprotein HBx may facilitate cancer progression. Gys2 overexpression can inhibit hepatocellular carcinoma progression whereas Gys2 knockdown advanced cancer development. We also applied oscillatory and impulse disturbance to p53 signaling pathway and the results showed that optimal p53-Gys2 negative feedback loop was highly resistant to oscillatory or impulse disturbances. Instead, the canonical p53-MDM2 negative feedback circuit can significantly affect the dynamics of p53 and therefore effectively shaped pulsatile patterns. Therefore, the dual negative feedback loops in p53 signaling can provide features of both robustness and tunability. These dynamic features are critical for cellular homeostasis against tumor progression in p53 signaling pathway.