MicroRNAs: Critical Regulators of Development, Cellular Physiology and Malignancy

Abstract

MicroRNAs (miRNAs) are 18-24 nucleotide RNA molecules that regulate the stability or translational efficiency of target mRNAs. These regulatory RNAs function by acting as sequence-specific guides which recruit a large protein complex known as the RNA-induced silencing complex, or RISC, to target mRNAs which are subsequently silenced. Diverse functions have been attributed to miRNAs including the regulation of cellular differentiation, proliferation, and apoptosis. Moreover, significant evidence has accumulated implicating a fundamental role for miRNAs in the development of cancer. We recently demonstrated that the oncogenic transcription factor c-Myc regulates a group of miRNAs known as the mir-17 cluster. This represents the first documented example of a mammalian transcription factor that regulates miRNA expression. Moreover, it was independently demonstrated that the mir-17 cluster accelerates c-Myc-induced lymphomagenesis in an in vivo mouse model. Together, these studies support an important role for this group of miRNAs in c-Myc-mediated tumorigenesis. We have also demonstrated that two miRNAs in this cluster regulate the pro-proliferative, pro-apoptotic transcription factor E2F1. Herein, we propose a model in which the mir-17 cluster prevents excessive E2F1 activity, and thereby apoptosis, in response to activation of c-Myc.