Table 1.
Justifications for logic functions used in Fig. 5, Model I. A number of literature citations are provided in the table55,78–85
| Regulatory logic rule | Justification |
|---|---|
| MYCt+1 = Growth Factor AND NOT Overpopulation AND NOT Hypoxia | Both overpopulation and hypoxia inhibit MYC expression. Hypoxia initiates the TGF-β pathway and promotes phosphorylation of SMAD’s MH2 domain, which inhibits MYC expression (Yagi, Furuhashi et al., 2002; Feng, Liang et al., 2002). Overpopulation activates the Wnt signaling pathway, releasing the APC destruction complex and promoting degradation of β-catenin, a transcriptional activator of MYC (Su, Fu et al. 2008). In contrast, growth factors activate MYC transcription via RAS signaling (Lewis, Shapiro, 1998). Our logic rule assumes that MYC activation (via growth factor induced signaling) is only possible when neither inhibitor (Overpopulation and Hypoxia) is active. |
| P27t+1 = Hypoxia OR NOTMYC t | Hypoxia activates P27, a potent cell cycle inhibitor, by initiating the TGF-β pathway and promoting phosphorylation of SMAD’s MH2 domain, which plays a role in maintaining P27 expression (Yagi, Furuhashi et al.2002; Feng, Liang et al. 2002). MYC, when active, inhibits transcription of P27 by binding to its promoter (Yang, Sheng, 2001). We assume there are endogenous levels of active P27 present in the absence of hypoxia. The OR NOT logic rule ensures that when present, Hypoxia’s activation of P27 dominates MYC’s inhibition. |
| Cyc-Cdkt+1 = NOT P27tAND NOT P53t | Cyclin dependent kinases (Cyc-Cdk) are inhibited by both P27 and P21. P21 is activated by P53 in response to DNA damage signals. For simplicity we have excluded P21 from this regulation (Baldin, V., J. Lukas, et al., 1993; Coqueret, 2003). |
| P53t+1 = DNA Damage | P53 is transcriptionally activated in the presence of DNA Damage (Lahav et al. 2004). |
| Proliferationt+1 = Cyc-Cdkt | Cyclin dependent kinases (Cyc-Cdk) are required for cell progression in the G1 phase. They act to inhibit the Rb protein by phosphorylation, which is an inhibitor of cell cycle progression and proliferation. (Baldin, V., J. Lukas, et al., 1993; Coqueret, 2003). |
| Apoptosist+1 = P53t | P53 transcriptionally activates BAX, which is an upstream activator of apoptosis (Basu and Halder, 1998). |