Post-Transcriptional Control of the Hypoxic Response by RNA-Binding Proteins and MicroRNAs

Abstract

Mammalian gene expression patterns change profoundly in response to low oxygen levels. These changes in gene expression programs are strongly influenced by post-transcriptional mechanisms mediated by mRNA-binding factors: RNA-binding proteins (RBPs) and microRNAs (miRNAs). Here, we review the RBPs and miRNAs that modulate mRNA turnover and translation in response to hypoxic challenge. RBPs such as HuR (human antigen R), PTB (polypyrimidine tract-binding protein), heterogeneous nuclear ribonucleoproteins (hnRNPs), tristetraprolin, nucleolin, iron-response element-binding proteins (IRPs), and cytoplasmic polyadenylation-element-binding proteins (CPEBs), selectively bind to numerous hypoxia-regulated transcripts and play a major role in establishing hypoxic gene expression patterns. MiRNAs including miR-210, miR-373, and miR-21 associate with hypoxia-regulated transcripts and further modulate the levels of the encoded proteins to implement the hypoxic gene expression profile. We discuss the potent regulation of hypoxic gene expression by RBPs and miRNAs and their integrated actions in the cellular hypoxic response.

Keywords: RNA-binding proteins; hypoxia; mRNA turnover; microRNAs; post-transcriptional gene regulation; ribonucleoprotein complex; translational control; untranslated regions.

Figure 1

Schematic of RBPs and microRNAs influencing the hypoxic response by HIF-1α. RBPs and microRNAs that interact with HIF-1α mRNA and modulate the production of HIF-1α protein in hypoxia. In the nucleus, HIF-1α transcriptionally upregulates the expression of target genes bearing hypoxia-response elements (HREs) in their promoters, including those that encode GLUT1 and VEGF mRNAs and those that encode microRNAs like miR-210 and likely also miR-373. In turn, miR-210 can modulate the production of HIF-1α by repressing the production of GPD1L; other RBPs and other microRNAs assist in modulating the expression of additional HIF-1α stability regulators (e.g., VHL, CUL2), and other hypoxia-response proteins like GLUT1 and VEGF.