Subtle alteration in microRNA dynamics accounts for differential nature of cellular proliferation

Abstract

In the G1 phase of the mammalian cell cycle, a bi-stable steady state dynamics of the transcription factor E2F ensures that only a certain threshold level of the growth factor can induce a high expression level (on state) of E2F to initiate either normal or abnormal cellular proliferation or even apoptosis. A group of microRNAs known as the mir-17-92 cluster, which specifically inhibits E2F, can simultaneously influence the threshold level of growth factor required for E2F activation, and the corresponding expression level of E2F in the on state. However, mir-17-92 cluster can function as either oncogene or tumor suppressor in a cell-type specific manner for reasons that still remain illusive. Here we put forward a deterministic mathematical model for Myc/E2F/mir-17-92 network that demonstrates how the experimentally observed mir-17-92 mediated differential nature of the cellular proliferation can be reconciled by having conflicting steady state dynamics of E2F for different cell types. While a 2-D bifurcation study of the model rationalizes the reason behind the contrasting E2F dynamics, an intuitive sensitivity analysis of the model parameters predicts that by exclusively altering the mir-17-92 related part of the network, it is possible to experimentally manipulate the cellular proliferation in a cell-type specific fashion for therapeutic intervention.