Figure 3

Interrogation of the ATM/p38 MAPK and p53 signaling pathway in GC. Ectopic expression (E1) represents gain-of-function (GoF) while knockdown (KO) represents loss-of-function (LoF) of the respective network element. The leftmost column shows the level of DNA damage with other molecules separated by a pink line. In contrast, the rightmost columns show the model outputs: proliferation, cell cycle arrest, and apoptosis. Each line represents a fixed point or steady state corresponding to the input. Light purple cells indicate a zero value (inactivation), while dark purple cells indicate activation (value 1). The first two fixed points are related to loss-of-function (LoF) of p53, that is, all node knockdown (KO) of p53. As you can see, only the ATM/p38 MAPK pathway is activated and triggers cell cycle arrest and apoptosis in response to DNA damage. The next two fixed points are described as loss-of-function (LoF) of p38 MAPK, that is, induction of proliferation. Apparently, the first fixed point knockdown (KO) of p38 MAPK represents a proliferation state due to the inactivation of DNA damage. Even in the presence of DNA damage, knockdown (KO) of p38 MAPK accelerated proliferation due to activation of cell cycle promoters such as E2F1, Myc, and CDK-cyclin complex. As you can see, loss-of-function (LoF) of p38 MAPK in response to DNA damage, lncRNA-GAS5 expression is accelerated but fails to trigger cell cycle arrest and/or apoptosis except in the proliferation state. After that, the other two fixed points represent the gain-of-function (GoF) of p38 MAPK, which means cell cycle arrest and apoptosis as well as activation of the p53 pathway. The ensuing fixed points are associated with gain-of-function (GoF) of p38 MAPK as well as loss-of-function of p53. Clearly, activation of the expression of the lncRNA-GAS5, miR-34c, p21, and RB1 triggers arrest and apoptosis (independently of p53). The other two following fixed points indicate the knockdown (KO) of ATM. Equally, this was observed in the loss-of-function (LoF) of p38MAPK. This means that at a certain point in the absence of DNA damage and another in response to DNA damage triggered proliferation; similarly, the lncRNA GAS was activated but refused to induce cell cycle arrest and apoptosis-like phenotypes. The other two fixed points of ATM represent the gain-of-function (GOF) of ATM, and then, more two fixed points (at last) represent the overexpression (E1) of ATM with p53 KO (knockdown), i.e., expression of the lncRNA-GAS5, miR-34c, p21, and RB1, induces cell cycle arrest and apoptosis (independently of p53). Yellow arrows represent upregulation, while the red arrows facing down represent downregulation, respectively.