Molecular Mechanisms Regulating mRNA Stability: Physiological and Pathological Significance

Abstract

The cytoplasmic level of a messenger RNA, and hence protein, depends not only upon its rates of synthesis, processing, and transport, but its decay rate as well. mRNA decay rates are frequently not static, but vary in response to extracellular stimuli and viral infections. Sequence elements within an mRNA, together with the protein and/or small noncoding RNA factors that bind these elements, dictate its decay rate. Not surprisingly, genetic alterations in mRNA stability can lead to various diseases, including cancer, heart disease, and immune disorders. However, we now have the capacity to alter selective aspects of the mRNA decay machinery by design in order to tune expression of any given gene to desired levels as a means of achieving therapeutic results. Our intent in this review is to introduce the reader to the intricacies of regulated gene expression at the level of mRNA stability, describe the roles of mRNA stability in pathology and drug development, and discuss some recent developments in the field of computational biology that are providing novel tools for understanding specific protein-RNA interactions, which drive the mRNA degradation machinery.

Chaperone Hsp27, a Novel Subunit of AUF1 Protein Complexes, Functions in AU-Rich Element-Mediated mRNA Decay

“…Here, we demonstrate activation-induced subunit rearrangements within ASTRC and identify chaperone Hsp27 as a novel subunit that is itself an ARE-binding protein essential for rapid ARE-mRNA degradation. As Hsp27 has well-characterized roles in protein ubiquitination as well as in adhesion-induced cytoskeletal remodeling and cell motility, its association with ASTRC may provide a sensing mechanism to couple proinflammatory cytokine induction with monocyte adhesion and motility.Many mRNAs encoding proteins transiently required for inflammatory responses, cell proliferation, and intracellular signaling are labile due to AU-rich elements (AREs) in their 3Ј untranslated regions (UTRs) (14,21,57). ARE association by ELAV-like (embryonic lethal, abnormal vision) proteins, such as HuR, blocks ARE-mediated mRNA decay (AMD) (31).…”

“…Many mRNAs encoding proteins transiently required for inflammatory responses, cell proliferation, and intracellular signaling are labile due to AU-rich elements (AREs) in their 3Ј untranslated regions (UTRs) (14,21,57). ARE association by ELAV-like (embryonic lethal, abnormal vision) proteins, such as HuR, blocks ARE-mediated mRNA decay (AMD) (31).…”

Upf1/Upf2 Regulation of 3′ Untranslated Region Splice Variants of AUF1 Links Nonsense-Mediated and A+U-Rich Element-Mediated mRNA Decay

“…The mRNAs that encode many cytokines, oncoproteins, growth factors, and signaling components are highly labile, providing a mechanism for rapidly changing mRNA levels in response to extracellular stimuli (50). Many of these mRNAs are targeted for rapid degradation by AϩU-rich elements (AREs) within their 3Ј-untranslated regions (3Ј-UTRs) (32,58). AREs range in length from 50 to 150 nt and often possess one or more copies of the AUUUA pentamer or UUAUUUA(U/A)(U/A) nonamer.…”

The interplay of HuR and miR-3134 in regulation of AU rich transcriptome

“…It is well documented that mRNA decay pathways play an important role in regulation of various transcripts involved in oncogenesis, inflammatory pathways, hypoxia regulation, and Alzheimers disease. 1,2 This underlines the importance to understand the mechanisms of transcript stability control. This work was undertaken to identify novel regulators of mRNA decay.…”

“…There are two well-known mechanisms for regulating the transcript turnover. The first one involves the A/Urich elements (ARE) and their binding proteins (ARE-BP), [1][2][3][4] whereas, the second one is mediated by microRNAs (miRNA). [5][6][7] Since both pathways act through conserved elements present in microRNAs and Au Rich element (ARe)-mediated degradation of transcripts are thought to be two independent means of gene regulation at the post-transcriptional level.…”