Translational control of hypoxia sensitive genes by nucleolin

Abstract

The first striking cellular response to hypoxia is the suppression of energy consuming processes, such as translation, protein degradation and transcription. Even though the metabolic rate is suppressed, several genes show an increased expression rate against the overall trend. In general, the alteration of gene expression can be modulated at transcriptional or posttranscriptional level. The latter involves alteration in mRNA-stability, translational efficiency or mRNA-localization. mRNA translation is a highly controlled process which is sensitive to a variety of cellular stressors. Here we introduce the collagen prolyl 4-hydroxylase alpha (I) (P4HA1) and MMP-9 as hypoxia sensitive genes, regulated by modulation of translational efficiency. In both cases the initial step in translational control is the increased binding of the RNA-binding protein nucleolin (~64 kDa form) at the 5′- and/or 3′ untranslated regions (UTR) of the mRNAs. The increased level of ~64 kDa nucleolin under hypoxia can be attributed to an autocatalytic cleavage of a high molecular weight form, without alterations in nucleolin mRNA-concentration. Thus, the alteration of translational efficiency by nucleolin, which occurs through a hypoxia inducible factor (HIF) independent pathway, is an important step in C-P4H-alpha (I) and MMP-9 regulation and highlights the role of translational control under hypometabolic conditions.