Page 15 - 72_04

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

abundance after infection; perhaps surprisingly, some of these
contain AU-rich instability elements (AREs) in their 3'-untranslated
regions. ARE-containing mRNAs normally undergo rapid decay;
however, their stability can increase in response to signals such as
cytokines and virus infection that activate the p38/MK2 mitogen-
activated protein kinase (MAPK) pathway. HSV-1 infection stabilizes
the ARE mRNA encoding the stress-inducible IEX-1 mRNA. Whether
the IEX-1 mRNA stabilization is carried out by vhs or through the
activation of p38 by ICP27 remains to be clarified (29).

The presence of AU-rich elements in the 3’UTR of viral genomes
adds an additional level of regulation. Thus, direct interactions
between RNA-binding proteins and viral RNA can alter viral RNA
stability and viral protein expression in a manner favorable for viral
survival. AU-rich elements have been identified in the late 3’UTR of
the human papilloma virus (HPV-1) and HPV31 genomes, in the E6
and E7 oncogenes of HPV-16, in the 3’UTR of hepatitis C virus and
certain alpaviruses and in the 5’UTR AU-rich region of the gag gene
of human immmunodeficiency virus (HIV-1). Several of these regions
are binding sites for HuR and the stability of the RNAs is inversely
proportional to the levels of cellular HuR expression (30).

Other diseases

Alterations in the regulation of mRNA stability processes in other
types of diseases have been reported as well. For instance, mutations
that increase mRNA degradation provoking the absence of factor
VIII mRNA (F8) in haemophilia A (31); binding of the Y box-binding
factor-1 (YB-1) to ARE in GM-CSF mRNA, enhancing GM-CSF-
dependent survival of eosinophils that are central in the pathogenesis
of asthma (32); polymorphisms between 2 ARE that increase protein
binding to the allele ARE2, causing a faster degradation of PPP1R3
mRNA that, in turn, lowers the concentration of the protein
implicated in insulin resistance, and thus increasing the risk for
development of type 2 diabetes (33); and finally, it has been found
reduced expression of sGC subunits in animal models of genetic
hypertension because of reduced binding to the mRNA-stabilizing
protein HuR compared to normal animals (34).

575