Circular reasoning: microRNAs and cell-cycle control

Abstract

MicroRNAs (miRNAs) have attracted considerable attention because of their important roles in development, normal physiology, and disease states including cancer. Recent studies have identified specific miRNAs that regulate the cell cycle and have documented that the loss or gain of miRNA-mediated cell-cycle control contributes to malignancy. miRNAs regulate classic cell-cycle control pathways by directly targeting proteins such as E2F transcription factors, cyclin-dependent kinases (Cdks), cyclins and Cdk inhibitors. Moreover, from recent findings, it has been suggested that miRNAs themselves might be subject to cell-cycle dependent regulation. Together, these observations indicate that the reciprocal control of RNA silencing and the metazoan cell cycle impacts cellular behavior and disease.

Figure 1. miR-17 family regulation of E2F activities

miR-17 family members are implicated in a complex regulatory circuit through which they modulate the effects of E2F transcription factors. The proto-oncoprotein c-Myc transcriptionally activates E2F1, E2F2 and E2F3 which, in turn, induce c-Myc expression. Likewise, E2Fs activate their own transcription. Unchecked, these reciprocal activations would result in a positive feedback cycle of E2F activity. Whereas moderate E2F activation results in cell proliferation, unconstrained activation can induce a protective apoptotic response. E2F signaling must therefore be tightly regulated and is held in check in part by the miR-17 family, whose members are induced both by c-Myc and by activating E2Fs.

Figure 2. microRNAs that regulate the G₁ to S transition

The decision to commit to DNA replication is made at the G1 to S transition. This event depends on regulated phosphorylation of the Rb pocket protein (green), resulting in the liberation of E2Fs (green) to activate gene expression required for S phase entry. Rb phosphorylation, in turn, depends on the coordinate regulation of cyclins (blue), cyclin-dependent kinases (blue), and Cdk inhibitors (yellow). Numerous miRNAs, including those shown here, have been implicated in the direct or indirect regulation of this cellular decision. It is important to note that the depicted regulatory relationships illustrate the control of regulatory complexes by miRNAs and are not intended to depict specific miRNA-target pairs.