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

responsible for mRNA degradation). More interesting will be the use
of sense-oriented ORNs that are no supposed to interact with the
homologous RNA but might compete for the sequestration of trans-
acting factor and exosome, inhibiting in this way the target mRNA
degradation (37).

The p38 MAPK signaling pathway plays an important role in
inflammation and other physiological processes. There are four p38
MAPKs: a and ß, which are 75% homologous, and ? and d wich are
more distant relatives. Inflamatory stimuli activate four major
intracellular signaling pathways: the nuclear factor-?B (NF?B)
pathways and the three MAPK pathways (ERK, JNK and p38). All
four drive transcription of inflammatory genes. The p38 pathway
is also involved in posttranscriptional regulation, and stabilizes
inflammatory response mRNAs and promotes their translation
through ARE in the 3’UTR of the mRNAs. Posttranscriptional
regulation of TNF-a and cyclooxygenase-2 mRNAs by p38 have been
extensively investigated and several examples were already shown
in this review. Because inhibiting p38 MAPK suppresses production
of key inflammatory mediators, it was obvious to search for
inhibitors of p38 MAPK for therapy of chronic inflammatory diseases
such as rheumatorid arthritis, Crohn’s disease, chronic obstructive
pulmonary disease and psoriasis. The most widely used are pyridinyl
imidazole compounds such as SB203580 and SB202190. The
potential of p38 as a drug target has led to development of large
collection of inhibitors by pharmaceutical companies. Preclinical
studies have largely used model of arthritis, and several inhibitors
are now in human trials. Adverse effects of inhibition are hard to
predict but immunosupression is likely. Targets upstream or
downstream could also be used to block the MAPK pathway although
to date they have not been reported (38).

Furthermore, a number of approaches that exploit RNA’s
structural dynamics and sequence-specific binding abilities (RNA
interference, antisense RNA) are already in place to modulate gene
expression. However, there is increasing need for developing
synthetic riboregulators that can be integrated into biological
networks to function with a wide array of genes and yield insights
into RNA-based cellular processes. Isaacs and colleagues were able
to engineer riboregulators that both repress and activate translation

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