MicroRNAs in stress signaling and human disease

Abstract

Disease is often the result of an aberrant or inadequate response to physiologic and pathophysiologic stress. Studies over the last 10 years have uncovered a recurring paradigm in which microRNAs (miRNAs) regulate cellular behavior under these conditions, suggesting an especially significant role for these small RNAs in pathologic settings. Here, we review emerging principles of miRNA regulation of stress signaling pathways and apply these concepts to our understanding of the roles of miRNAs in disease. These discussions further highlight the unique challenges and opportunities associated with the mechanistic dissection of miRNA functions and the development of miRNA-based therapeutics.

Figure 1

miRNAs can regulate stress signaling pathways and thereby modify stress-related phenotypes through a number of distinct mechanisms, some of which are schematized here. A miRNA can perform a stress signal mediation function (A) in which it acts as a critical intermediate in a signaling pathway or it may act as a stress signal modulator (B) in which it titrates a signaling intermediate. A miRNA may participate in a negative (C) or positive (D) feedback loop which serves to dampen or amplify a signal, respectively. Lastly, a miRNA may target both positive and negative regulators of a pathway (E), thereby buffering pathway activity from stochastic fluctuation. For each mode of regulation, the consequences of deletion of the miRNA on pathway activity are schematized on the right.

Figure 2

miRNAs that promote or inhibit tumorigenesis provide diverse functions within oncogenic and tumor suppressor signaling pathways. (A) miR-34 family members and the miR-17-92 cluster function as signal mediators for the p53 and Myc pathways, respectively. (B) miR-16 negatively regulates multiple components of mitogenic pathways and thereby provides an inhibitory signal modulation function. (C) miR-146a is activated by NF-κB signaling and negatively feeds back on the pathway by repressing upstream activators of NF-κB. In this capacity, miR-146a restrains excessive NF-κB activity which can lead to tumorigenesis. (D) Let-7, miR-21, and the miR-143/145 cluster participate in positive feedback loops which function to stably enforce cellular transformation programs upon activation of oncogenes such as NF-κB, Kras, and Myc. (E) miR-26 can repress both pro-tumorigenic targets (cyclins D2 and E2) and anti-tumorigenic targets (PTEN). These opposing activities endow miR-26 with context-dependent positive or negative effects on tumorigenesis.

Figure 3

Examples of miRNAs that function in cardiac stress signaling pathways. (A) miR-29 and miR-15 family members act as mediators of stress signaling pathways that regulate fibrosis and cardiomyocyte proliferation and survival, respectively. (B) miR-208a and miR-126 titrate regulators of cardiac remodeling and angiogenesis and thereby function as stress signal modulators. (C) miR-133a directly targets its activator SRF and in this manner restrains excessive SRF activity in adult cardiomyocytes which can lead to heart failure. (D) miR-21, miR-199a, and the miR-23a/27a/24-2 cluster participate in positive feed back loops which serve to stably activate signaling pathways that lead to pathologic cardiac remodeling and angiogenesis. (E) The miR-143/145 cluster targets both positive and negative regulators of smooth muscle differentiation. Through this buffering activity, these miRNAs maintain the characteristic phenotypic plasticity of this cell type, allowing smooth muscle cells to proliferate in response to injury.