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