---
id: "edwards-2007-rna-tumour"
title: "RNA Tumour Viruses"
authors:
  - "Dustin C. Edwards"
  - "Susan J. Marriott"
venue: "The Cancer Handbook"
year: 2007
date: "2007-10-15"
doi: "10.1002/9780470025079.chap06.pub2"
url: "/research/publications/10-1002-9780470025079-chap06-pub2/"
pdf: "/research/publications/10-1002-9780470025079-chap06-pub2/dustin-edwards-10-1002-9780470025079-chap06-pub2.pdf"
openAccess: false
citedBy: 0
citedBySource: "OpenAlex, read 2026-09-12"
---
# RNA Tumour Viruses

Textbook chapter on RNA tumour viruses, focused on HTLV-1 Tax.

## Abstract

It is estimated that 15% of all cancer cases are aetiologically linked to viral infection. In these cancers, genomic instability and subsequent multi‐step tumourigenesis is associated with the expression of viral oncoproteins. Human T‐cell leukaemia virus type‐I (HTLV‐I), a prototypic representative of the RNA tumour viruses, is linked to the development of adult T‐cell leukaemia. The HTLV‐I oncoprotein, Tax, targets the regulators of cell cycle progression and DNA repair, leading to cellular transformation.

## Full text

Machine-extracted from the PDF linked above. It carries the artifacts that come with reading a typeset two-column page: running heads, figure captions in the flow of the prose, and words broken across line ends. The abstract above is the registry's deposit and is the authoritative text.

RNA Tumour Viruses
Dustin C. Edwards and Susan J. Marriott
Baylor College of Medicine, Houston, TX, USA
INTRODUCTION TO RNA TUMOUR VIRUSES
Worldwide, it is estimated that 15% of cancer cases are aeti-
ologically linked to viral infection, accounting for nearlly
1.5 million new cases and 900 000 deaths annually (Butel,
2000). For most human cancers, the precise cause of tumouri-
genesis is unknown, although epidemiologic studies have
linked infection by specific DNA- and RNA-containing
viruses to the development of particular cancers. In viral-
associated human cancers, genomic instability and sub-
sequent multi-step tumourigenesis is associated with the
expression of viral oncoproteins. Thus, oncogenic viruses
provide an opportunity to directly investigate molecular and
cellular mechanisms that lead to cancer. This chapter will
focus predominantly on RNA viruses that cause cancer in
humans.
Human RNA Tumour Viruses
Of the human RNA viruses, human T-cell leukaemia virus
type-I (HTLV-I) and hepatitis type-C virus (HCV) of the
retroviridae and flaviviridae families, respectively, have been
established as transforming viruses. HTLV-I is the aetiologic
agent of adult T-cell leukaemia (ATL), a disease character-
ized by malignant proliferation of CD4+ T lymphocytes that
develops in a small percentage of HTLV-I-infected individ-
uals (Kondo et al., 1987). Although acute HCV infection
often causes only mild illness, it has become increasingly
evident that HCV is responsible for substantial morbidity
and mortality, particularly from chronic liver disease and
hepatocellular carcinoma (Liang et al., 2004) (see Liver,
Gallbladder, and Extrahepatic Bile Ducts). Here, we will
discuss retroviruses as the prototypic representatives of the
RNA tumour viruses. Animal retroviruses induce cellular
transformation via several distinct mechanisms: transduction
of proto-oncogenes, proviral integration adjacent to proto-
oncogenes, trans-activation or repression of cellular gene
expression, and disruption of cell cycle control and DNA
repair, each of which promote viral efforts to drive replica-
tion of the proviral genome.
Overview of Retroviral Replication
Retroviruses bind to specific cellular receptors and follow-
ing internalization and uncoating, the viral-encoded reverse
transcriptase transcribes the viral genomic RNA into single-
stranded complementary deoxyribonucleic acid (cDNA) and
subsequently into double-stranded deoxyribonucleic acid
(dsDNA) (Figure 1). After completing dsDNA synthesis, the
viral DNA translocates to the nucleus, and integrates, usually
randomly, into the host chromosomal DNA. The integrated
viral genome, also known as the provirus, then replicates
during cellular division. The retroviral genome encodes the
structural and enzymatic genes gag, pro, pol, and env and
is flanked on the 5′ and 3′ ends by non-coding long ter-
minal repeats (LTRs) composed of U3, R, and U5 regions.
The LTRs contain promoter elements and RNA processing
signals that are necessary for viral gene expression. Cellu-
lar machinery is required for viral genes to be transcribed,
spliced, and exported to the cytoplasm where they are trans-
lated into precursor proteins. Assembly of progeny virions
from these precursor proteins occurs coincident with packag-
ing of two copies of the single-stranded viral RNA genome.
Virion budding and release from the cell is followed by the
proteolytic cleavage of precursor proteins to form mature
virions (reviewed in Goff, 2001).
Role of Retroviral Replication in Tumourigenesis
Retroviruses have been identified in almost all animal
species and many have been shown to transform cells in
culture and/or cause tumours in animals. Most transforming
retroviruses mediate this effect through the action of cellular
oncogenes. Transforming retroviruses fall into two groups:
transducing retroviruses (e.g., Rous sarcoma virus), which
carry a proto-oncogene within their genomes, and cis-
activating retroviruses (e.g., avian leukosis virus and mouse
mammary tumour virus), which lack a proto-oncogene, but
The Cancer Handbook 2nd Edition. Edited by Malcolm R. Alison
 2007 John Wiley & Sons, Ltd.

2 THE MOLECULAR AND CELLULAR BASIS OF CANCER
Nucleus
Cytoplasm
RNA
Reverse
transcription
cDNA
dsDNA
Provirus Cellular
DNA
mRNA
mRNA
Proteins
Virus particle
Figure 1 Retrovirus life cycle.
stimulate transformation by integrating in the vicinity of a
cellular oncogene and activating the expression of nearby
genes. A proto-oncogene is a normal cellular gene that, when
altered by mutation or aberrant regulation, becomes an active
oncogene. More than 30 oncogenes encoded by transducing
retroviruses have been identified and more than 70 proto-
oncogenes have been shown to be regulated by insertion of
cis-activating retroviral proviruses (Rosenberg and Jolicoeur,
1997). In addition to expression or activation of oncogenes,
viral regulatory proteins that function primarily to enhance
transcription from the viral LTR, such as HTLV-I Tax, have
been shown to dysregulate several cellular processes and lead
to tumour formation (Yoshida, 2005).
HUMAN TUMOURIGENIC RETROVIRUSES: HTLV-I
HTLV-I, the first discovered pathogenic human retrovirus,
is now recognized as the causative agent of ATL and
tropical spastic paraparesis/human T-cell leukaemia virus
type-I–associated myelopathy (TSP/HAM), a progressive
neurological inflammatory syndrome (Gessain et al., 1985).
HTLV-I has also been associated with other clinical dis-
orders including HTLV-I-associated arthropathy, HTLV-I-
associated uveitis, infective dermatitis, and polymyositis
(Buggage, 2003; Nicot, 2005; Watanabe, 1997).
Transmission of HTLV-I
The nature of HTLV-I transmission is an important factor
in the development of ATL. The most efficient transmis-
sion of HTLV-I occurs from infected to uninfected cells
via a virologic synapse (Igakura et al., 2003). Cell contact
induces cytoskeletal polarization of the infected cell at the
cell–cell junction. Viral proteins and genomic RNA accu-
mulate at the junction and are transferred to the target cell.
The virus integrates randomly into host chromosomes and
the HTLV-I provirus, in both asymptomatic viral carriers
and ATL patients, is detected almost exclusively in CD4+ T
lymphocytes. However, other haematopoietic cells, includ-
ing non-CD4+ T lymphocytes, B lymphocytes, monocytes,
macrophages, and dendritic cells, also help maintain HTLV-
I infection during the lifespan of an individual (reviewed
in Manel et al., 2005). Over the course of infection, expan-
sion of a subset of infected CD4+ T lymphocytes containing
one or a few clonally integrated HTLV-I proviruses adds to
the population of oligoclonally infected cells (Eiraku et al.,
1998). Individual behaviours and exposure routes have been
associated with transmission of HTLV-I: parenteral trans-
mission by blood transfusion, mother-to-infant transmission
through breast-feeding, and sexual intercourse. Each mode
of transmission is distinct and the disease outcome appears
to vary, depending on the route of transmission.
Transmission by Blood Transfusion
Intravenous routes, such as blood transfusion, appear to be
the most efficient modes of HTLV-I transmission. Parenteral
transmission of the virus from donor to recipient requires live
infected lymphocytes (Kannagi et al., 2004). In retrospec-
tive studies of transfusion patients who received HTLV-I-
contaminated blood products, 40–60% were seropositive by
2 months post-transfusion (Manns et al., 1992). There is also
a high HTLV-I seroprevalence among intravenous drug users
who share contaminated needles and syringes. Although
blood-mediated transmission of HTLV-I-infected lympho-
cytes is an important risk factor for TSP/HAM, patients
developing ATL following blood transfusion is rare (Gout
et al., 1990).
Mother-to-child Transmission
Mother-to-child transmission of HTLV-I occurs when an
infant ingests infected milk-borne lymphocytes during pro-
longed breast-feeding. This route of transmission is asso-
ciated with the development of ATL (Kannagi et al., 2004).
Twenty percent of children born of HTLV-I–infected women
are seropositive. The risk of vertical transmission correlates
with maternal proviral load and antibody titer (Ureta-Vidal
et al., 1999). After HTLV-I antibody screening was intro-
duced as part of standard prenatal care in Japan, seropositive
mothers were counselled to discontinue breast-feeding and
the rate of infection in infants fed on artificial milk was
significantly reduced (Hino et al., 1997). The risk of infec-
tion by other routes of mother-to-child transmission, such as
intrauterine or peri-partum, is low, possibly due to HTLV-
I–induced apoptosis of placenta cells (Fujino et al., 2000).
Sexual Transmission
Behaviours associated with sexual transmission of the virus
parallel those of other sexually transmitted diseases: inter-
course without condom use and having multiple or casual
partners. The efficiency of sexual transmission is due to the
presence of HTLV-I–infected lymphocytes in the semen of
seropositive males. Female sexual partners of infected males
often become HTLV-I sero-positive and the cross-sectional

RNA TUMOUR VIRUSES 3
studies indicate that in most endemic areas, male-to-female
transmission occurs at a higher frequency than in the reverse
(Roucoux et al., 2005). However, female-to-male transmis-
sion may occur by transmission of infected cells through
injured mucous membranes. As with viral transmission by
blood transfusion, individuals infected with HTLV-I by sex-
ual transmission have a lower risk of developing ATL than
those infected by mother-to-child transmission.
Global Epidemiology of HTLV-I
Epidemiological aspects of HTLV-I have been thoroughly
and continuously studied since the virus was first identified in
1980. Initial screens for virus infection typically utilize sero-
logical assays such as enzyme-linked immunosorbent assays
(ELISA), western blotting, and indirect immunofluorescence
to detect antibodies to viral proteins. In addition to testing
for sero-conversion, polymerase chain reaction (PCR) assays
are usually used as confirmatory assays to identify HTLV-I
proviral DNA.
Geographic Prevalence
It is currently estimated that 10 to 20 million people world-
wide are infected with HTLV-I (Edlich et al., 2003). The
virus is endemic in regions of southern Japan, Africa, Cen-
tral and South America, the Caribbean, Eastern Europe,
and the southeastern United States (Bangham, 2000). The
sero-prevalence rate differs by geographic area, socio-
demographic composition, and individual risk behaviours.
For example, up to 10% of the general population in south-
western Japan is seropositive for HTLV-I, yet the sero-
prevalence rate is as high as 37% in small, selected pop-
ulations from this region (Yamaguchi, 1994; Mueller et al.,
1996). In addition, indicators of lower socio-economic status,
such as education and income, are associated with HTLV-I
infection. In non-endemic regions, such as North America
and Europe, the virus is detected primarily in immigrants
from endemic areas, intravenous drug users, and sex work-
ers. Overall, the sero-prevalence of HTLV-I in non-endemic
regions is low (e.g., <0.006% in Norway, France, and Greece
and <0.03% in the United States and Canada) (Proietti
et al., 2005).
Individual Prevalence
HTLV-I sero-prevalence rates correlate strongly with the
age and sex of an individual, with the greatest number of
virus carriers being females, 40 to 50 years of age. The age-
dependency is attributed to reduced chances of viral exposure
in younger individuals. Reduced HTLV-I sero-prevalence in
certain regions of the world has been attributed to modified
sexual behaviour (increased condom use) and breast-feeding
practices (increased popularity and feasibility of artificial
milk). The 1.6-fold greater sero-prevalence rate in females
can be attributed to the greater efficiency of male-to-female
0 5 9 kb
gag
pro
pol
env
IV
III
II
I
tax
rex
LTR LTR
U3
R U5
X region
TRE
Figure 2 Genome structure of HTLV-I.
sexual transmission. Although there is an imbalance of sero-
prevalence between males and females, the incidence of ATL
is comparable in both sexes.
Viral Gene Expression
HTLV-I Genome
HTLV-I is an enveloped retrovirus with a diploid, positive-
sense RNA genome that is 9032 nucleotides in length
(Figure 2) (Seiki et al., 1984). Like all known replication-
competent retroviruses, the HTLV-I genome contains the
gene sequence LTR-gag-pol-env-LTR. The presence of addi-
tional regulatory genes within a pX region located 3′ of the
env gene, characterizes HTLV-I as a complex retrovirus,
distinct from other non-human retroviruses. The X region
contains four open reading frames (ORFs), two of which [rex
(ORF III) and tax (ORF IV)] encode regulatory proteins that
are critical for HTLV-I replication and viral transforming
ability. Rex is a 27-kDa protein that modulates the transport
of unspliced and single-spliced viral RNA from the nucleus
to the cytoplasm. By physically and temporally controlling
the amount of viral RNA that is exported to the cytoplasm for
translation, Rex can regulate the switch between latent and
productive phases of the viral life cycle. The 40-kDa Tax
protein is a potent trans-activator of viral gene expression.
In addition, Tax activates the transcription of numerous cel-
lular genes and is the major transforming protein of HTLV-I.
Microarray analyses revealed over 300 genes that are upreg-
ulated in Tax-expressing cells (Pise-Masison et al., 2002).
Transcriptional Regulation
HTLV-I contains a single viral promoter located within the
U3 region of the LTR. The promoter contains three imper-
fectly conserved 21 base pair repeats called Tax respon-
sive elements (TREs). The TREs contain core sequences
with homology to consensus cellular cyclic adenosine
monophosphate-responsive elements (CREs) and are flanked
by G/C rich sequences (Connor et al., 2000; Cox et al.,

4 THE MOLECULAR AND CELLULAR BASIS OF CANCER
1995; Jeang et al., 1988; Paca-uccaralertkun et al., 1994).
Importantly, Tax does not directly bind to DNA. Instead,
Tax interacts with cellular transcription factors and coactiva-
tors to alter their DNA binding affinity and specificity. For
example, Tax enhances the dimerization of cyclic adenosine
monophosphate-response element binding protein (CREB)
and increases its affinity for the imperfect viral CRE, but
not the consensus cellular CRE (Adya et al., 1994; Cohen-
Fix et al., 1996; Kwok et al., 1996). The Tax-CREB-CRE
complex creates a high affinity target site for recruitment of
the cellular coactivators CREB binding protein (CBP) and
its homologue, p300. The ability of Tax to directly interact
with CREB and CBP/p300 allows this complex to bypass the
normal cAMP signalling pathway and activate transcription
from the viral LTR in the absence of CREB phosphorylation
(Van Orden et al., 2000).
RNA Processing
Synthesis of viral mRNA from an integrated proviral DNA
results in a single primary transcript that can be directed
to multiple pathways (Figure 3). A portion of these 8.5-kb
transcripts is exported to the cytoplasm, where they are either
packaged as genomes into progeny virions or are translated
to Gag-Pro and Gag-Pro-Pol polyproteins. Alternatively, the
transcript may be spliced in a Rex-dependent manner to
form subgenomic mRNAs that encode the overlapping genes
env, rex, and tax. Env is encoded on a 4.2-kb single-spliced
transcript, while rex and tax are encoded on a 2.1-kb double-
spliced transcript. Unlike Tax, Rex regulates viral gene
expression at the post-transcriptional level by influencing
the ratio of unspliced to spliced mRNA exported to the
cytoplasm. The effects of Rex are mediated by a specific
205 nucleotide cis-acting Rex response element (RRE) in
the 3′ region of the viral RNA. The RRE forms a stable
and complex secondary structure, consisting of multiple stem
loops, which is recognized by Rex. Early after infection,
little Rex is available and double-spliced viral transcripts are
efficiently transported to the cytoplasm to produce rex/tax
Nucleus
Cytoplasmgag pol env tax/rex
Splicing and transport
gag pol
env
gag
pol
env
Early eventsLate events
tax/rex
Rex
Tax
Figure 3 Transcriptional trans-activation and viral RNA processing.
mRNA. Translation Tax greatly increases viral transcription.
However, increased Rex expression exerts negative feedback
control that decreases the export of double-spliced rex /tax
mRNA in favour of unspliced and single-spliced mRNAs
encoding viral structural proteins.
Adult T-cell Leukaemia (ATL)
HTLV-I infection is associated with the development of ATL,
an aggressive, clonal malignancy of mature T lymphocytes,
which develops in a small percentage of HTLV-I-infected
individuals (Kondo et al., 1987). Disease onset occurs after
a long period of clinical latency, consistent with a multi-step
process of T lymphocyte immortalization and transformation.
Leukaemic Cells
ATL is characterized by malignant proliferation of mature
T lymphocytes with a phenotype of CD2+, CD3+, CD4+,
CD8−, and HLA-DR+. Diagnostic criteria for ATL include
incidental detection of leukocytosis, increased serum lactate
dehydrogenase (LDH) levels, morphologically atypical lym-
phocytes with convoluted or lobulated nuclei, seropositivity
for HTLV-I proteins, and detection of monoclonal or oligo-
clonal integrated provirus (Green et al., 2001; Nicot, 2005).
In addition, HTLV-I-transformed cells express surface mark-
ers associated with T-cell activation, including interleukin-2
receptor alpha (IL-2Rα), transferrin receptor, and major his-
tocompatibility complex class-II (MHC-II) molecules (Green
et al., 1989; Green et al., 2001). HTLV-I–transformed cells
also display increased expression of cellular genes that reg-
ulate T-cell growth and proliferation, including granulocyte-
macrophage colony stimulating factor (GM-CSF), tumour
necrosis factor-alpha (TNF-α), interleukin-15 (IL-15) and
IL-2 (Azimi et al., 1998; Ballard et al., 1988; Green et al.,
2001; Mariner et al., 2001; Uchiyama et al., 1985). Although
leukaemic cells from ATL patients express high levels of IL-
2 and its receptor, these cells are mostly unresponsive to
this cytokine and proliferate continuously in the absence of
exogenous IL-2 (Maeda et al., 1985; Popovic et al., 1984).
Clinical Features
ATL can be classified into three clinical phases: acute, smoul-
dering, and chronic phases. Smouldering and chronic phases
of ATL are less aggressive than the acute phase of disease and
are characterized by skin lesions and low levels of circulating
lymphocytes. During chronic ATL, an increase in circulating
leukaemic cells accounts for an increased leukocyte count.
Patients in both the smouldering and chronic phases of ATL
can progress into acute ATL within a period of months. In
acute ATL, patients exhibit hypercalcaemia, lymphadenopa-
thy, skin lesions due to leukaemic cell infiltration, leuko-
cytosis, eosinophilia and neutrophilia, hepatosplenomegaly,
hyperglycaemia, and renal failure. Expansion of a clonally
infected CD4+ T lymphocyte population occurs during this
phase (Eiraku et al., 1998). Although the provirus remains

RNA TUMOUR VIRUSES 5
integrated in the host genome, viral gene expression is not
detectable. The prognosis of patients with acute ATL is
poor, with a mean survival time of 6 months, following
diagnosis (Green et al., 2001; Nicot, 2005). Patients are typ-
ically infected early in life and disease onset occurs after a
period of several decades (Wilks et al., 1996). Opportunistic
infections are a major complication due to the immunocom-
promized state of ATL patients. Common infections include
Pneumocystis carinii pneumonia, cytomegalovirus pneumo-
nia, aspergillosis, candidiasis, and Strongyloides stercoralis
infection (Greenberg et al., 1990; Newton et al., 1992; Nicot,
2005; Pagliuca et al., 1988; Roudier et al., 1997; Tobi-
nai et al., 1991). Common opportunistic malignancies of
ATL patients include Kaposi sarcoma and Epstein-Barr
virus–associated lymphoma (Greenberg et al., 1990; Tobinai
et al., 1991).
HTLV-I Tax and Mechanisms of Transformation
Unlike transducing or cis-acting retroviruses, HTLV-I does
not encode a proto-oncogene and has not been associ-
ated with proviral insertion that activates the expression of
flanking cellular oncogenes. Instead, extensive studies have
demonstrated that the viral-encoded Tax protein, which is
responsible for trans-activation of the viral promoter, is the
major transforming protein. The role of Tax in leukaemoge-
nesis was initially suggested by experiments in which rodent
fibroblasts became morphologically transformed following
Tax expression (reviewed in Feuer et al., 2005). Subse-
quently, Tax was shown to induce tumours in transgenic
animals, and immortalize human T-cells. For example, deliv-
ery of Tax by a transformation-defective Herpes saimiri virus
vector immortalized primary human T lymphocytes in vitro,
and these transformed cells resembled the leukaemic pheno-
type of HTLV-I-infected T-cells from patients (Grassmann
et al., 1989). Together, these studies have shown that Tax is
sufficient for cellular transformation.
Interestingly, only a small percentage of leukaemic cells
isolated from ATL patients express Tax. In these cells, Tax
expression is low and typically can be detected only by
PCR. Tax is expressed early after infection, before viral gene
expression is downregulated by Rex-mediated suppression.
As such, Tax is believed to play a role in the initiation
of transformation. Whether Tax expression is required to
maintain transformation remains to be determined. Anti-
sense oligonucleotides designed to reduce Tax expression
in tumour cell lines from Tax transgenic mice did not
affect the rate of cell growth or tumour formation in vivo,
despite a 90% reduction in Tax expression (Kitajima et al.,
1992). Thus, Tax expression may not be required to maintain
the transformed state. However, HTLV-I–transformed Rat1
cells that no longer express Tax, lost the ability to form
tumours in nude mice, and reintroduction of the tax gene
restored the ability of these cells to form tumours, suggesting
that Tax is required to both establish and maintain cellular
transformation (Yamaoka et al., 1992). Although there is no
clear consensus, the cumulative results indicate that Tax may
contribute to the initiation of the transformation process but
may not be required to maintain the transformed state.
Transcriptional Activation and Repression
One of the proposed mechanisms of Tax-mediated cellular
transformation is transcriptional activation of cellular genes
involved in proliferation and regulation of cellular processes.
In addition to altering the DNA binding affinity and speci-
ficity of bZIP transcription factors, such as CREB, Tax also
activates promoters that contain binding sites for the NF-κB
family of transcription factors (Figure 4). Tax activates the
NF-κB pathway by inducing IκB Kinase-dependent phospho-
rylation of the inhibitor of NF-κB, IκB, causing it to release
NF-κB so that it can be translocated to the nucleus and
can activate the cellular gene expression (Carter et al., 2001;
Suzuki et al., 1995; Xiao et al., 2000). As with CREB, Tax-
mediated NF-κB activation bypasses signalling pathways that
normally regulate NF-κB activity.
In addition to the CREB and NF-κB pathways, Tax also
activates genes regulated by the serum response factor (SRF)
pathway. Genes with serum response elements (SREs) within
their promoters are normally activated by the binding of SRF
to a core DNA sequence, the CArG box, within the SRE. SRF
then associates with ternary complex factors (TCFs) that bind
to adjacent Ets-binding sites, also within the SRE. Tax has
been shown to interact with both SRFs and TCFs to enhance
their affinity for the SRE (Fujii et al., 1992; Fujii et al., 1995;
Shuh et al., 2000). Tax also affects SRE trans-activation due
to its interaction with, and recruitment of, the coactivators
CBP/p300 and p/CAF.
Despite being best known as a transcriptional activator,
Tax can also repress transcription of cellular genes, in partic-
ular those involved in DNA repair and cell cycle checkpoint
regulation. Transcriptional repression by Tax appears to be
a consequence of some of the same mechanisms that induce
transcriptional activation. For example, since Tax is known
CBP/p300 Tax
CREB
NF-kB
SRF
Trans-activation
Tax
Trans-repression
CBP/p300
Tax
p53
NF-kB
p65
P
via kinase
Figure 4 Tax-mediated transcriptional trans-activation or trans-repression
of cellular genes.

6 THE MOLECULAR AND CELLULAR BASIS OF CANCER
to bind CBP/p300, it can sequester these important coactiva-
tors away from promoters that do not contain TREs, resulting
in repressed expression of CBP/p300 dependent genes. For
instance, Tax competes with E-box–binding members of the
β helix-loop-helix transcription factor family for recruitment
of CBP/p300 (Colgin et al., 1998). DNA polymeraseβ, lck,
bax, p53, p18INK4c, and p19 INK4d , all of which contain E-box
elements in their promoters, have been shown to be repressed
by Tax (Akagi et al., 1996; Suzuki et al., 1999a; Suzuki
et al., 1999b). In addition, Tax inhibits p53-dependent trans-
activation of cellular promoters by competitively binding and
sequestering CBP, which is required for p53-mediated trans-
activation. The repression of p53-mediated transcription by
Tax is, however, more complex than simple sequestration of
CBP/p300. Tax also represses p53-mediated transcription in
an NF-κB –dependent manner by inducing p53 phosphoryla-
tion, which alters the ability of p53 to interact with a variety
of transcription factors (Jeong et al., 2004). Tax-induced loss
of p53 function inhibits G1/S checkpoint arrest, p53-mediated
apoptosis, and DNA repair.
Deregulation of Cell Cycle Checkpoint Controls
Separate from its effects on transcription regulation, Tax also
interferes with normal regulation of cell cycle checkpoints
via protein–protein interactions (Figure 5). During G1 phase
of the cell cycle, cyclin D forms an active complex with
Cdk4 or Cdk6. The cyclin D/Cdk4/6 complex phosphorylates
retinoblastoma (Rb), which, in its hypo-phosphorylated state,
is bound to the transcription factor E2f. Rb phosphorylation
releases E2f, enabling transcriptional activation of genes that
promote cell cycle progression into S phase. Tax modulates
this transition by two mechanisms. First, Tax directly inter-
acts with cyclin D3, cyclin D2, Cdk4, and Cdk6, thereby
stabilizing cyclin/Cdk complexes. This induces earlier onset
of cyclin D/Cdk4/6 kinase activity and subsequent accumu-
lation of hyper-phosphorylated Rb in Tax-expressing cells
G1 phase
Tax
cyclin D/Cdk4/6
E2fRb
P
P
P
S phase
Rb E2f
p15
INK4bp16
INK4a
Tax
p21
Waf1/
Cip1
p18
INK4cp19
INK4d
Chk1
Tax
G2/M phase
Tax
p53
p53
Cdc25A
Cdc25A
PP
Figure 5 Tax-mediated dysregulation of cell cycle checkpoint controls.
(Haller et al., 2002). Second, Tax binds directly to hypo-
phosphorylated Rb to facilitate its proteasomal degradation
(Kehn et al., 2005). Through these mechanisms, the early
release of E2f in Tax-expressing cells truncates G1 phase,
interferes with checkpoint control, and accelerates cell cycle
entry into S phase (Lemoine et al., 2001).
Repair of DNA damage prior to DNA synthesis in S
phase is critical for accurate genome replication. Typically,
activation of p53 in response to DNA damage regulates cell
cycle progression between G1 and S phases by delaying
S phase entry and allowing time for DNA repair to occur
prior to DNA replication. p53-dependent transcriptional
activation of Cdk inhibitors (CKIs), such as p21Waf1 /Cip1 ,
p27Kip1 , p15INK4b, p16INK4a , p18INK4c, and p19INK4d , blocks
cyclin–Cdk kinase activities, resulting in cell cycle arrest
at the G1/S transition (Morgan, 1995; Peter et al., 1994;
Sherr et al., 1995). The inactivation of p53 function by Tax
interferes with these normal p53 activities, which allows cells
to bypass the G1/S checkpoint and enter the S phase where
damaged DNA can be replicated.
The ability of Tax to activate expression of the Cdk
inhibitor p21Waf1 /Cip1 in a p53-independent manner appears
to conflict with the inhibition of p53-dependent p21Waf1 /Cip1
expression by Tax. However, p21Waf1 /Cip1 is unique among
the CKIs because it can bind to and stabilize cyclin-
dependent kinase (CDK) complexes, such as cyclin D–Cdk4,
and increase their kinase activity (Haller et al., 2002). There-
fore, Tax-mediated activation of p21Waf1 /Cip1 expression
increases the steady state levels of active cyclin D–Cdk4
and enhances Rb phosphorylation, allowing E2f release and
activation of genes that promote cell cycle progression. Thus,
even though p21Waf1 /Cip1 is a cell cycle inhibitor, its activa-
tion by Tax may contribute to the accelerated progression
of cells through G1 phase and through the DNA dam-
age –induced G1/S checkpoint (Akagi et al., 1996; Cereseto
et al., 1996; De La Fuente et al., 2000; Hatta et al., 2002).
Tax also interferes with the function of other CKIs.
For example, the binding of Tax to the Cdk4/6 inhibitors,
p15INK4b and p16INK4a , obstructs their ability to block kinase
activity (Hatta et al., 2002; Iwanaga et al., 2001; Low et al.,
1997; Suzuki et al., 1996). Tax also represses the transcrip-
tion of p18INK4c and p19INK4d resulting in decreased activity
of these cell cycle inhibitors (Suzuki et al., 1999a). Together,
these effects stimulate cell cycle progression by Tax.
DNA damage –induced cell cycle arrest can also occur at
the G2/M checkpoint. Following DNA damage, signalling
cascades involving Chk1 and Chk2 activate several down-
stream targets including p53 (G1 cell cycle arrest), Cdc25
(S phase delay), and Cdc25A/C (G2 arrest). Phosphorylation
of Cdc25A by Chk1 targets it for proteasomal degradation
thereby inhibiting activation of the Cdk1/2 complex, which is
required for progression through S phase and G2/M check-
points. Tax physically interacts with Chk1 and inhibits its
ability to phosphorylate p53 (Park et al., 2004). In addition,
Cdc25A degradation is blocked in Tax-expressing cells, lead-
ing to attenuation of G2 cell cycle arrest. Although Tax binds
to Chk2, and this complex co-localizes at sites of DNA dam-
age (Haoudi et al., 2003), a function for this complex remains
to be determined.

RNA TUMOUR VIRUSES 7
Inhibition of DNA Repair and Promotion of Chromosome
Instability
Cellular transformation is frequently associated with genome
instability and HTLV-I-transformed lymphocytes isolated
from ATL patients as well as Tax-transformed cells in culture
display a wide range of chromosome abnormalities, including
duplications, deletions, translocations, rearrangements, and
aneuploidy (Whang-Peng et al., 1985). Despite the compli-
cated karyotypes observed in ATL patients, no specific chro-
mosomal defect or mutation has been consistently associated
with this leukaemia. Although Tax enacts pleiotropic dys-
regulation of cellular functions, there is no evidence that Tax
directly induces DNA damage (Kao et al., 1999). Instead,
Tax appears to inhibit the ability of cells to repair DNA
damage, resulting in an increased mutation frequency.
The cellular response to DNA damage is mediated
through multiple functionally overlapping pathways, includ-
ing nucleotide excision repair (NER), base excision repair
(BER), mismatch repair (MMR), and double-strand break
repair (DSBR). Tax suppresses some of these pathways,
which likely increases the incidence of genomic muta-
tions and contributes to Tax-mediated cellular transformation
(Figure 6). For example, the ability of Tax to suppress NER
correlates with its ability to trans-activate the expression
of proliferating cell nuclear antigen (PCNA) (Ressler et al.,
1997; Kao et al., 1999; Lemoine et al., 2000). PCNA is a
trimeric sliding clamp cofactor that increases the processiv-
ity of DNA polymerase δ during DNA replication and repair.
PCNA overexpression, alone, is able to promote DNA syn-
thesis past template lesions, resulting in increased nucleotide
mis-incorporation by DNA polymerase δ (Mozzherin et al.,
1996; Mozzherin et al., 1997). By increasing PCNA expres-
sion, Tax appears to reduce the fidelity of DNA polymerase
δ during DNA replication and promote the introduction of
mutations into the chromosomes of HTLV-I–infected cells.
Tax also dysregulates DNA repair pathways by inhibiting
BER, in part by repressing transcription of DNA poly-
merase β, an essential enzyme involved in base excision
and mismatch forms of DNA repair (Jeang et al., 1990).
BER removes a variety of DNA lesions caused by sponta-
neous hydrolytic depurination, deamination of cytosine and
5-methylcytosine, products of reactions with hydroxyl free
radicals, and covalent DNA adducts.
Tax
p53
Pol b
PCNA
p21
Waf1/
Cip1
BER
NER
DNA
replication
Figure 6 Tax-mediated inhibition of DNA repair and promotion of
genomic instability.
The ability of Tax to suppress NER and BER, together
with the abundance of chromosomal aberrations observed
in Tax-expressing cells, suggests that Tax affects genome
stability by multiple and, probably, overlapping mechanisms.
Disruption of the mitotic spindle checkpoint (MSC) is
associated with altered chromosome structures and numbers
(Lavia et al., 2003). The MSC regulates cell cycle transition
from metaphase to anaphase and is mediated by numerous
protein groups, including mitotic arrest defective (MAD-
1, -2, -3) proteins, budding uninhibited by benzimidazoles
(BUB-1, -2, -3), monopolar spindle (Mps-1), and anaphase
promoting complex (APC) (Abrieu et al., 2001; Cohen-Fix
et al., 1996; Hoyt et al., 1991; Li et al., 1991). The MSC is
activated in response to DNA damage and, once activated,
arrests the cell cycle prior to anaphase to ensure proper
chromosome alignment before segregation. Malfunction of
the MSC can result in improper sister chromatid separation
and can lead to loss or gain of genetic material. Tax directly
interacts with MAD-1 and APC to interfere with the activities
of both proteins, resulting in multi-nucleation and delayed
mitotic transition (Jin et al., 1998; Liu et al., 2005).
Dysregulation of human telomerase reverse transcriptase
(hTERT) provides another opportunity to generate chromo-
somal abnormalities in Tax-expressing cells. hTERT adds
specific nucleotide repeat sequences, known as telomeres,
to the ends of chromosomal DNA. Telomeres prevent both
the fusion of chromosomal ends and their degradation by
exonucleases. In the absence of hTERT, telomere shortening
occurs, allowing end-to-end chromosomal fusion and forma-
tion of dicentric chromosomes that are vulnerable to breakage
during mitosis. This can lead to aneuploidy or chromosomal
rearrangements and translocations. hTERT expression is ele-
vated in most cancer cells, including leukaemic ATL cells
(Franzese et al., 2002; Tsumuki et al., 2001; Uchida et al.,
1999). However, Tax represses hTERT expression during
mitogenic stimulation, while activating hTERT expression
in the absence of mitogenic stimulation (Gabet et al., 2003;
Sinha-Datta et al., 2004). Reduced hTERT expression after
T-cell stimulation can cause a transient state of genomic
instability that is relieved when the mitogenic stimulus is
removed. The biological advantage of hTERT repression for
HTLV-I, if any, remains to be determined. However, activa-
tion of hTERT by Tax upon removal of the mitogenic signal
may offer a long-term proliferative advantage to cells that
have acquired chromosomal abnormalities.
CONCLUSION
For several decades, RNA tumour viruses, including HTLV-
I, have been intensely studied because of their association
with human cancers and their usefulness as model sys-
tems in which to study processes of cellular transformation.
The HTLV-I Tax oncoprotein contributes to tumourigenesis
by interfering with cellular transcription regulation, tumour
suppressor function, cell cycle regulation, and DNA repair
(Figure 7). Alteration of the host environment appears to
be an incidental result of viral genome replication efforts

8 THE MOLECULAR AND CELLULAR BASIS OF CANCER
MAD
APC
P53
Target function EffectsTarget molecules
Transcription
activation
Transcription
repression
Cell-cycle
dysregulation
DNA repair inhibition
Genomic instability
CBP/p300
cyclin D/Cdk4/6
HTLV
-I
IL
-2
TNF
-a
DNA polymerase b
P53
p18tt
E2f
Rb
PCNA
p21
Waf1/
Cip1
p15
INK4b p16
INK4a
p18
INK4c p19
INK4d
Chk1
Active cyclin D/Cdk4
Repression of
cell cycle inhibitorsp53
Suppression of NER and BER
Multi -nucleation
Delayed mitotic transition
Aneuploidy
hTERT
PCNA
CBP/p300
PCAF
CREB
NF-kB
SRF
Figure 7 Pleiotropic effects of Tax.
that indirectly allow an accumulation of somatic mutations
and genomic instability. It is almost certain that continued
study of HTLV-I–mediated transformation will provide new
insight into the roles of viral and cellular factors in trans-
formation and may reveal new basic cellular mechanisms of
carcinogenesis.
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