Regulation of Messenger RNA Stability Provides Another Control Mechanism

Although most mRNAs in mammalian cells are very stable (half-lives measured in hours), some turn over very rapidly (half-lives of 10-30 minutes). In certain instances, mRNA stability is subject to regulation. This has important implications since there is usually a direct relationship between mRNA amount and the translation of that mRNA into its cognate protein. Changes in the stability of a specific mRNA can therefore have major effects on biologic processes.

Messenger RNAs exist in the cytoplasm as ribonu-cleoprotein particles (RNPs). Some of these proteins protect the mRNA from digestion by nucleases, while others may under certain conditions promote nuclease attack. It is thought that mRNAs are stabilized or destabilized by the interaction of proteins with these various structures or sequences. Certain effectors, such as hormones, may regulate mRNA stability by increasing or decreasing the amount of these proteins.

It appears that the ends of mRNA molecules are involved in mRNA stability (Figure 39-19). The 5'

cap structure in eukaryotic mRNA prevents attack by 5' exonucleases, and the poly(A) tail prohibits the action of 3' exonucleases. In mRNA molecules with those structures, it is presumed that a single endonucleolytic cut allows exonucleases to attack and digest the entire molecule. Other structures (sequences) in the 5' non-coding sequence (5' NCS), the coding region, and the 3' NCS are thought to promote or prevent this initial endonucleolytic action (Figure 39-19). A few illustrative examples will be cited.

Deletion of the 5' NCS results in a threefold to fivefold prolongation of the half-life of c-myc mRNA. Shortening the coding region of histone mRNA results in a prolonged half-life. A form of autoregulation of mRNA stability indirectly involves the coding region. Free tubu-lin binds to the first four amino acids of a nascent chain of tubulin as it emerges from the ribosome. This appears to activate an RNase associated with the ribosome (RNP) which then digests the tubulin mRNA.

Structures at the 3' end, including the poly(A) tail, enhance or diminish the stability of specific mRNAs. The absence of a poly(A) tail is associated with rapid degradation of mRNA, and the removal of poly(A) from some RNAs results in their destabilization. His-tone mRNAs lack a poly(A) tail but have a sequence near the 3' terminal that can form a stem-loop structure, and this appears to provide resistance to exonucle-olytic attack. Histone H4 mRNA, for example, is degraded in the 3' to 5' direction but only after a single endonucleolytic cut occurs about nine nucleotides from the 3' end in the region of the putative stem-loop structure. Stem-loop structures in the 3' noncoding sequence are also critical for the regulation, by iron, of the mRNA encoding the transferrin receptor. Stem-loop structures are also associated with mRNA stability in bacteria, suggesting that this mechanism may be commonly employed.

Coding

AUUUA

Figure 39-19. Structure of a typical eukaryotic mRNA showing elements that are involved in regulating mRNA stability. The typical eukaryotic mRNA has a 5' noncoding sequence (5' NCS), a coding region, and a 3' NCS. All are capped at the 5' end, and most have a polyadenylate sequence at the 3' end. The 5' cap and 3' poly(A) tail protect the mRNA against exonuclease attack. Stem-loop structures in the 5' and 3' NCS, features in the coding sequence, and the AUrich region in the 3' NCS are thought to play roles in mRNA stability.

Other sequences in the 3' ends of certain eukaryotic mRNAs appear to be involved in the destabilization of these molecules. Of particular interest are AU-rich regions, many of which contain the sequence AUUUA. This sequence appears in mRNAs that have a very short half-life, including some encoding oncogene proteins and cytokines. The importance of this region is underscored by an experiment in which a sequence corresponding to the 3' noncoding region of the short-half-life colony-stimulating factor (CSF) mRNA, which contains the AUUUA motif, was added to the 3' end of the P-globin mRNA. Instead of becoming very stable, this hybrid P-globin mRNA now had the short-half-life characteristic of CSF mRNA.

From the few examples cited, it is clear that a number of mechanisms are used to regulate mRNA stability—just as several mechanisms are used to regulate the synthesis of mRNA. Coordinate regulation of these two processes confers on the cell remarkable adaptability.

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Diabetes 2

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