Figure 9
From: Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery
a. This model is similar to the one in figure 1, but a few more details concerning N-myc activation are added. The transforming event of figure 1 is constitutively on when Shh is high, so it is not shown here. Tumor growth requires Nmyc-P and either Gli1 or Gli2 to be active. b. the feedback loop shown as a dotted line from Gli1 to Ptc1 is inactive. The drug suppresses Gli1 and Gli2 activity downstream of Smo, inhibiting tumor growth, but high Smo levels allow continued expression of Gli2, which is able to activate the cell cycle. Only when high drug doses are present are Gli1 and Gli2 sufficiently suppressed to stop tumor growth. c. The feedback loop is now active; Gli1 and Gli2 are suppressed by the drug, but small levels of Gli1 are sufficient to activate Ptc1 production, supressing Smo expression, hence Gli2 is lower. As drug dose increases, Gli1 is suppressed and eventually Ptc1 production stops, allowing Smo to be expressed.