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

binding to mRNAs encoding proteins involved in malignant
transformation, and inducing or repressing their expression by
altering mRNA stability and/or translation rates. Moreover, the
cytoplasmic abundance of AUBPs (e.g., HuR and AUF1) increases
with malignancy (6, 17). This is particularly relevant since the
cytoplamic presence of AUBPs seems to be linked to its stabilizing/
destabilizing function. Wnt activation, the tumor suppressor protein
von Hippel Lindau (VHL), and AMP-activated protein kinase (AMPK)
are responsible for the cytoplasmic distribution of AUBPs and
their pathways are also altered in cancer (18-20). Posttranslational
modifications of RNA-binding proteins can affect their ability to
bind to target mRNAs as well as their subcellular location as it
has been shown with the phosphorylation of AUF1 and KSRP. Cell
signaling events may also alter mRNA stability, translation and AUBP
abundance. For instance, the MAPK pathway affects mRNA stability
and translations through the differential phosphorylation of RNA-
binding proteins (21). Importantly, several RNA-binding proteins can
bind to a common ARE-containing target mRNA on both distict,
nonoverlapping sites, and on common sites in a competitive fashion.
For instance, IL-8 plays an integral role in promoting the malignant
phenotype in breast cancer and its production is directly influenced
by inflammatory cytokines in the tumor microenvironment. In
keeping with this notion, activation of the IL-1 receptor on malignant
breast cancer cells strongly induced IL-8 mRNA levels. HuR, KSRP
and TIAR were found to bind to one or more locations within the IL-
8 3’UTR although the association of the stabilizing factor HuR was
20-fold greater than that of the destabilizing factor KSRP (22).

Inflamation and autoimmunity

Several proteins that are encoded by ARE-containing transcripts
are critical components of the effector phase of inflammatory
and autoimmune diseases. Of particular importance is tumor
necrosis factor a (TNF-a), one of the principal mediators of the
inflammatory response in mammals. In addition to its well-known
role in acute septic shock, it has been implicated in the pathogenesis
of graft-versus-host disease, rheumatoid arthritis, Crohn’s disease,
and the cachexia that accompanies cancer and the acquired

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