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Cell Cycle 9:16, 3135-3136; August 15, 2010; © 2010 Landes Bioscience
CELL CYCLE FEAturE
CELL CYCLE FEAturE
Cervical cancer, a human papillomavirus
(HPV)-induced malignancy, is the most
common gynecological cancer worldwide.
Infection of cervical epithelium with high-
risk HPV subtypes-16 and -18 followed by
HPV integration into the host genome
allows for constitutive expression of viral
oncoproteins. The early viral proteins E6
and E7 play a central role in cellular trans-
formation by inactivating the p53 and
pRb tumor suppressor pathways, respec-
tively. The oncogenic functions of E6
occur through its interaction with cellu-
lar regulatory proteins and one of the best
characterized E6-binding partners is the
E6-associated protein (E6-AP). E6-AP is
a member of the HECT ubiquitin-protein
ligase family and its interaction with E6
promotes enhanced degradation of p53 via
the ubiquitin-proteasome pathway.1 The
E6/E6-AP complex also mediates degra-
dation of NFX1, a transcriptional repressor
of human telomerase reverse transcriptase
(hTERT), leading to activation of hTERT
gene expression.2 These combined actions
facilitate HPV-mediated cellular trans-
formation in part by impeding cells from
reaching replicative senescence.
We have recently characterized a novel
cellular control mechanism that interferes
with the E6/E6-AP circuit leading to an
inhibition of cell proliferation and induc-
tion of senescence in HPV-transformed
cells.3 This process is governed by the
(TTP; also known as TIS11 and ZFP36),
which is the founding member of the
TIS11 family of RNA-binding proteins
that includes BRF-1 and BRF-2. TTP
is best known for its ability to act as a
Tristetraprolin and E6-AP
Killing the messenger in cervical cancer
Sandhya Sanduja and Dan A. Dixon*
Department of Biological Sciences and Cancer research Center; university of South Carolina; Columbia, SC uSA
Key words: HPV, E6-AP, tristetraprolin, AU-rich element, senescence
*Correspondence to: Dan A. Dixon; Email: email@example.com
Submitted: 07/08/10; Accepted: 07/09/10
Previously published online: www.landesbioscience.com/journals/cc/article/12951
Feature on: Sanduja S, et al. Aging (Albany NY) 2009; 1:803–17.
mRNA decay factor that binds to AU-rich
elements (ARE) present in the 3' untrans-
lated region (3'UTR) of many mRNAs
and this interaction targets the bound
mRNA for rapid degradation via the
ARE-mediated decay pathway.4 Through
this ability to regulate expression of a vari-
ety of ARE-containing mRNAs encoding
growth factors, inflammatory cytokines
and proto-oncogenes, such as tumor
necrosis factor-α (TNFα), cyclooxygen-
ase-2 (COX-2) and vascular endothelial
growth factor (VEGF), TTP serves a criti-
cal role in maintaining normal cellular
physiology by exerting anti-inflammatory
and anti-neoplastic effects.
Messenger RNA turnover is a tightly
regulated process and its deregulation can
contribute to disease pathogenesis. Our
group and others have shown that loss
of TTP expression is a consistent feature
occurring in a variety of malignancies,
including cervical cancer, implicating
TTP as a potential tumor suppressor.3,5,6
Furthermore, TTP expression has been
shown to be growth inhibitory in colon
and mast cell tumor models, and can
sensitize cells to apoptosis.6,7 To investi-
gate the possible link between TTP and
cervical cancer, we examined the effects
of TTP re-expression on cellular prolifera-
tion in HPV18-transformed HeLa cervi-
cal cancer cells. TTP expression resulted
in a dramatic reduction in cell growth
accompanied with cellular changes char-
acteristic of a senescent phenotype.3 In
TTP-expressing cells, increased p53 pro-
tein expression along with reduced levels
of hTERT was observed and these studies
revealed that TTP’s presence promoted
p53 protein stabilization and inhibited
hTERT gene transcription. Interestingly,
TTP did not target viral gene transcripts
for degradation, but did bind and pro-
mote rapid decay of the ARE-containing
mRNA of E6-AP. This lack of E6-AP
ubiquitin ligase rescued p53 from E6/
E6-AP-mediated proteasomal decay path-
way and inhibited hTERT gene expression
ultimately leading to cellular senescence
(Fig. 1). Together, these findings provide
strong evidence that TTP can act as a
tumor suppressor by attenuating patho-
genic ARE-containing gene expression
and our findings in cervical cancer cells
demonstrate this aspect of TTP function.
This example identifying TTP as a
new player in cervical cancer strength-
ens the importance of regulated mRNA
turnover in disease and tumorigenesis, yet
some questions still remain unanswered.
For instance, is loss of TTP expression a
cause or a consequence of HPV infection
and what are the underlying mechanisms
promoting TTP silencing in tumors?
Studies examining rheumatoid arthritis
have implicated specific single nucleotide
polymorphisms in the TTP (ZFP36) gene
to impact its expression.8,9 Additionally,
studies in breast cancer demonstrate an
inverse relationship between miR29a lev-
els and TTP, suggesting that loss of TTP
expression in breast tumors may occur via
a microRNA-based mechanism.10 More
recently, DNA methylation of the TTP
promoter has been shown to regulate TTP
expression in response to TGFβ signal-
ing in hepatocellular carcinoma.11 While
these genetic and epigenetic mechanisms
give insight into the regulation of TTP
3136 Cell Cycle Volume 9 Issue 16 Download full-text
expression, which of these events prevail in
cervical cancer remains to be determined.
Finally, we believe that the link between
TTP and HPV-mediated events of cellular
transformation provides new insights into
the pathology of HPV-induced malignan-
cies and opens new therapeutic avenues
that utilize the cells own ability to target
and destroy cancer-associated messengers.
This work was supported by the National
Institutes of Health (R01CA134609) and
American Cancer Society (RSG-06-122-
Figure 1. ttP-mediated regulation of E6-AP and induction of cellular senescence. the binding
of ttP to the ArE-containing mrNA of E6-AP targets it for rapid degradation and subsequently
counteracts HPV-mediated proteosomal decay of p53 and activation of hTERT transcription lead-
ing to cellular senescence.
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