Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model
Fig 7
Different therapeutic interventions to restore TSP-1 level in Myc-induced tumors.
(A) Hyperactivity of Myc is simulated by increasing its rate of production (baseline rate multiplied by 5), which results in a significant downregulation of TSP-1 protein level. Experimental evidence indicates that Myc expression could be 2–10 times higher in tumor samples compared with control samples [99–102]. (B) The effect of TSP-1 repression by Myc overexpression is less obvious in hypoxia. (C) In the cases of Myc hyperactivity, knockdown of Myc synthesis (protein synthesis rate reduced to 10% of the hyperactive value) leads to a more notable increase in TSP-1 protein abundance in normoxia compared to hypoxia. (D) Hyperactive Myc engages both the direct transcriptional and posttranscriptional pathways (miRs) to repress TSP-1 protein expression. (E) Simulating the application of a Myc inhibitor at different doses under the condition of Myc hyperactivity. (F) Simulating the application of a miR-18a antagonist at different doses under the condition of Myc hyperactivity. Simulation results suggest that miR antagonists reach a maximum efficacy at around 40 nM. (G) Direct transcriptional stimulation by different doses of TGFβ results in a significant early increase in TSP-1 protein expression under Myc hyperactivity compared to the other two strategies. (A-G) Results are normalized with respect to the normoxic steady-state values calculated with baseline Myc synthesis rate. (E-F) The simulations assume that Myc inhibitors potently bind and sequester cytoplasmic Myc with a Kd of 1 nM, and that miR-18a antagonists bind and sequester miR-18a RISC with a Kd of 1 nM [103].