“Myc’ed Messages”: Myc Induces Transcription of E2F1 while Inhibiting Its Translation via a microRNA Polycistron

Abstract

The recent revelation that there are small, noncoding RNAs that regulate the expression of many other genes has led to an exciting, emerging body of literature defining the biological role for these molecules within signaling networks. In a flurry of recent papers, a microRNA polycistron induced by the oncogenic transcription factor c-myc has been found to be involved in an unusually structured network of interactions. This network includes the seemingly paradoxical transcriptional induction and translational inhibition of the same molecule, the E2F1 transcription factor. This microRNA cluster has been implicated in inhibiting proliferation, as well as inhibiting apoptosis, and promoting angiogenesis. Consistent with its seemingly paradoxical functions, the region of the genome in which it is encoded is deleted in some tumors and overexpressed in others. We consider the possibility that members of this polycistronic microRNA cluster help cells to integrate signals from the environment and decide whether a signal should be interpreted as proliferative or apoptotic.

MicroRNA profile analysis of human prostate cancers

“…Although differential expression of coding mRNA between normal and malignant tissues may differ by orders of magnitude, relatively modest differences of 1-to 2-fold, or less, were commonly seen for individual miRNAs. 5,31,32 This consideration, together with unique technical features in our analysis, may explain the comparatively modest differential T/N expression ratios observed in our study.…”

MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F, and Myc

“…5 could explain an experimental observation that seemingly contradicts the prediction of the model at steady state. Several groups (14,25,26) have shown that miR-20a and miR-17-5p (members of the miR-17-92 cluster) are antiapoptotic because the down-regulation of these miRs leads to increased cell death and their overexpression decreases cell death. These observations were explained (25,27) in terms of the down-regulation of E2F1 protein levels by miR-20a and miR-17-5p, and E2F1's induction of apoptosis when overexpressed.…”

“…6). Here, we focus on miR-17-92, which behaves as an oncogene or a tumor suppressor in different situations (2,14).…”

“…Gene expression data show over-expression of miR-17-92 in several tumors, including cancers of the breast, lung, colon, stomach, pancreas, and prostate (16,17). Although the tumor-suppressor property of miR-17-92 remains to be demonstrated directly in vivo, the following observations are quite suggestive: This cluster is deleted in 16.5% of ovarian cancers, 21.9% of breast cancers, and 20% of melanomas (14,15).…”

microRNAs and death receptors

“…Although E2F2 and E2F3 are also negatively regulated by miR-17-5p and miR-20a, E2F1 is more strongly affected [88]. The antiapoptotic activity of miR-17-92 miRNAs has been proposed to reflect the distinct physiological roles of different E2Fs in apoptosis [89]. Unlike E2F2 or E2F3, E2F1 has been particularly associated with apoptosis in addition to its function as an activator of cell cycle [90].…”