Fig. 5 miRNA (mir-17-92) governs the G1-S transition by influencing bi-stable E2F1 dynamics.(a) E2F steady state dynamics as a function of growth factor level from a two-component network. M1, M2, and M3 represent decreasing miRNA activity. Adapted from 83. (b)Differential E2F steady state dynamics as a function of miRNA level for varying miRNA efficacy obtained using the Myc/E2F/miR-17-92 network. Adapted from Sengupta, Govindaraj, and Kar 2018.84(Solid arrows represent the activation process and round-headed arrows represent the inhibition process.)
Experimental studies have shown that the expression level of E2F1 during ON state, can drive the cell to any one of the states such as quiescence, proliferation, and apoptosis82 and miR-17-92 components fine-tune the E2F expression.79,80 Studies have shown that either overexpression or downregulation of miR-17-92 cluster components can lead to unwanted cell proliferation and cancer.78Aguda et al83 proposed a model to explain these counterintuitive phenomena using a two-component network with E2F and miR-17-92 (Fig. 5a ). Their model proposed that the expression level of mir-17-92 cluster components can modulate the growth factor threshold for E2F activation and ‘ON’ state E2F level (Fig. 5a, right panel ), thus leading to different cellular states such as quiescence, proliferation, and apoptosis.83 They suggest that the cells can enter into the cancer zone if the E2F ‘ON’ level lies between proliferation and apoptosis zone.83Thus, upregulation of miRNA can allow the cells to escape apoptosis and become cancerous, and downregulation of miRNA can lead to unwanted proliferation.
Sengupta et al84 proposed an alternative mechanism for differential miRNA regulation of E2F based on the miRNA efficiency.84 They proposed a detailed model for Myc/E2F/mir-17-92 network (Fig. 5b ) considering all possible positive and negative feedback interactions to explain the differential E2F regulation by miR-17-92. They predict that by modulating the miRNA related parameters such as miRNA mediated target degradation and translation repression rate, the model can be fine-tuned to give rise to two different scenarios as shown in Fig. 5(b) : (i) increase in E2F expression and (ii) decrease in E2F level, with an increase in miRNA level.84 This explains why in certain solid cancers and some hematopoietic cancer types,78,85–99the overexpression of mir-17-92 components leads to increased proliferation, however, the same causes suppression of proliferation for certain hematopoietic cancer types.78,100–102