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VOL. 72 (4), 563-581, 2006 ABERRANT MRNA STABILITY REGULATION IN HUMAN...

The posttranscriptional processes that affect the mRNA are
regulated by the orchestrated interactions between mRNA structural
components (cis elements) and specific trans-acting factors. Well-
characterized RNA sequence elements can be found throughout the
body of mRNAs including the 5’-untranslated region (5’UTR), the
coding region, and the 3’UTR (Fig. 1A). Most RNA sequence elements
[e.g., the 5’-cap structure and the 3’poly(A) tail] are universally
present in all mRNAs and direct constitutive processes without
apparent selectivity of one mRNA relative to another. However,
specific RNA elements have been identified which affect the stability
and/or translation of given subsets of mRNAs. The vast majority of
such specific RNA sequences are present in the 3’UTR; among them,
the best characterized are regions rich in adenine and uridine
residues known as AU-rich elements (ARE). AREs have been
identified in the 3’UTR of a variety of short-lived mRNAs, including
those encoding oncogenes and growth factors, cell-cycle regulatory
proteins, cytokines, and inflammatory mediators. AREs frequently,
though not always, contain a variable number of AUUUA pentamers,
sometimes harbored within a U-rich region. The canonical motifs
identified for RNA-biding proteins HuR and TIA-1 (6, 7) consist of
a combination of primary sequence and secondary structure in the
3’UTR. AREs are well known to influence stability and are
increasingly recognized to affect translation (8, 9). The RNA levels
of many of ARE-containing mRNAs are altered in pathological
situations such as cancer and inflammation due to abnormal mRNA
stabilization and /or translation processes. It is crucial, therefore, to
understand the regulation of these «ARE-containing genes» because
of their demonstrated involvement in human diseases (2-5).

Cis-elements serve as binding sites for a variety of RNA-binding
proteins that modulate posttrancriptionally mRNA levels. Of
particular interest for this review is the family of RNA-binding
proteins that associate to the ARE-determinants (AUBPs). AUBPs
regulate, among other processes, the mRNA stability (in a positive
way such as the mRNA-stabilizing HuR or negative, like the mRNA-
destabilizing AUF1 and TTP) and translation (e.g., TIA inhibiting
translation or HuR, enhancing mRNA translation) of ARE-containing
mRNAs. At least 12 ARE-BPs (see Table 1) have been identified so
far. Most AUBPs are predominantly nuclear proteins that shuttle

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