Abstract IA1: Physiological and pathological functions of microRNAs

Abstract

Abstract microRNAs have emerged as major regulators of the functions of genes in multicellular organisms. They generally and perhaps always act as reducers of the protein output from a given mRNA allotment generated from a particular gene. However, when acting on mRNAs that function in a regulated pathway, they can either inhibit or augment the output from that pathway depending on whether they act on inhibitory gene transcripts or activating gene transcripts. We have concentrated on miRs that function within the circuitry of the hematopoietic system, focusing on those that impinge on innate and adaptive immune responses. We have found that miR-146a acts as a classic negative regulator of inflammation while miR-155 acts as a positive regulator by targeting inhibitory proteins. A miR that has particularly interested us recently is miR125b, which both acts during the development of hematopoietic cells from the hematopoietic stem cell and modulates the function of myeloid cells. In all of this work, we have relied on mouse knockouts, siRNA knockouts and overproducing constructs to probe miR function and have been impressed by the ease with which these genetic manipulations can lead to hyperproliferation and cancer. Overexpression of miR-125b leads to particularly rapid induction of very aggressive tumor cells that can be of either the myeloid or lymphoid lineage. The developmental origin of these tumors is under investigation. microRNAs have been seen as modulators of gene expression. Because it is becoming clear that they are so powerful in their physiological and pathological properties, it seems more appropriate to now consider them as co-regulators of gene expression, partners with transcription factors in determining the functional outcome of developmental and regulatory pathways. Citation Format: David Baltimore. Physiological and pathological functions of microRNAs [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA1.