Download Review article Cell transformation by animal papillomaviruses

Journal of General Virology (1992), 73, 217-222. Printed in Great Britain
217
Review article
Cell transformation by animal papillomaviruses
M . Saveria Campo
The Beatson Institute for Cancer Research, Cancer Research Campaign Beatson Laboratories, Garscube Estate,
Glasgow G61 1BD, U.K.
Because of the clinical importance of papillomavirus
infections, and the risk of malignant progression of some
of the lesions induced by this group of viruses (zur
Hausen, 1991), the study of their transformation potential and characteristics acquires particular importance.
Although in recent years experimental systems have
been developed which allow investigation into in vitro
cell transformation by human papillomaviruses (HPVs),
the first steps in the molecular aspects of cell transformation were made with animal papillomaviruses, first and
foremost bovine papillomavirus type l (BPV-1). In
addition animal systems have highlighted the interaction
between virus and cofactors in oncogenesis, and have the
unique advantage over the human one that direct
experimentation is feasible. Thus, BPV-4-associated
carcinogenesis of the alimentary canal of cattle (Jarrett et
al., 1978) has been experimentally reproduced both in
cattle (Campo & Jarrett, 1987) and in mice (Gaukroger et
al., 1991). Furthermore, Ito & Evans (1961) showed that
naked DNA of cottontail rabbit papillomavirus (CRPV)
was infectious and oncogenic, thus leading to the
detailed investigation of CRPV-associated tumorigenesis in several laboratories (Nasseri & Wettstein, 1987;
Brandsma et al., 1991).
In this brief review, which is not intended to be
comprehensive of all the work done on animal papillomaviruses, I shall focus on three animal models: cattle,
rabbit and monkey, and their respective viruses. A
comparison of the transformation characteristics of these
viruses within this group and with the human viruses will
show that the same end product, cell transformation, can
be achieved by employing different strategies.
Different papillomaviruses have different cell transformation potentials (Table 1). Some viruses can fully
transform primary cells with no need for additional
oncogenes; these viruses are chiefly the fibropapillomaviruses, such as BPV-1 and -2 (Morgan & Meinke, 1980;
Jarrett, 1985). Other viruses, such as the high-risk genital
HPVs, of which only HPV-16 will be discussed here, and
rhesus monkey papillomavirus (RhPV), can fully transform primary rodent kidney cells only in cooperation
0001-0629 © 1992 SGM
Table 1. Potential of papillomaviruses for
immortalization~transformation of primary cells
BPV-1
RhPV-1
HPV-16
BPV-4
CRPV
Full transformation of primary bovine and rodent
fibroblasts.
Activatedras required for full transformationof primary
baby rodent kidneycells.
Immortalizationof murine and humanprimarykeratinocytes and fibroblasts; activated ras required for full
transformationof primary baby rodent kidneycells and
human keratinocytes,and for partial transformationof
primaryhumanfibroblasts.
Activated ras required for partial transformation of
primary bovine fibroblasts.
Two-step transformationof sflEp cells.
with another oncogene, typically activated ras (Matlashewski et al., 1987; Schneider et al., 1991). Primary
human cervical keratinocytes are fully transformed by
HPV-16 and ras (DiPaolo et al., 1989), whereas in the
same conditions primary human fibroblasts are only
partially transformed (Matlashewski et al., 1988). However, HPV-16 can immortalize murine and human
primary keratinocytes and fibroblasts with no requirement for another oncogene (Pirisi et al., 1987; Matlashewski et al., 1988). These immortalized cells are not
tumorigenic in vivo, and are therefore considered
premalignant. More information about the immortalizing and transforming capability of HPV-16 can be
obtained in a recent review by DiMaio !~.!,991). BPV-4
cannot immortalize primary bovine fibroblasts by itself,
and requires the presence of activated ras to transform
them partially; these cells are not tumorigenic (Jaggar et
al., 1990). The low immortalization/transformation
potential of BPV-4 may be due to the lack of one of the
viral oncogenes (see below). CRPV does not require
additional oncogenes for transformation of sflEp rabbit
keratinocytes, but the transformation process goes
through two clearly defined steps: increased growth
potential and morphological transformation proper
(Meyers & Wettstein, 1991).
RhPV is the best qualified as a model for human
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218
M.S.
Campo
Table 2. Effect o f CRP V late region on cell transformation
5' L 2 0 R F
3' L 1 0 R F
N I H 3T3
sflEp
Inhibitory
No effect
N o effect
Essential
Table 3. Cell transformation by BPV-4
In vivo
Present in papillomas, absent in carcinomas; ras gene
amplified and activated in carcinomas.
In vitro
Necessary for initiation of transformation but absent in
transformed cells; ARS sequences and oncogenes amplified in transformed cells.
genital papillomaviruses. As shown by Ostrow et al.
(1990), it infects the genital tract, its presence is
associated with various degrees of dysplasia and neoplasia, its in vitro transformation characteristics are very
similar to those of HPV-16 (Schneider et al., 1991), and
the two genomes are very close in evolutionary terms
(Ostrow et al., 1991). It is interesting that a papillomavirus isolated from skin lesions of a colobus monkey is
related to the human cutaneous viruses HPV-5 and -8
(Kloster et al., 1988), and a papillomavirus isolated from
the papillary lesions of the oral cavity of pigmy
chimpanzees is related to HPV-13 (Van Ranst et al.,
1991), the agent of oral focal epithelial hyperplasia in
humans (Pfister et al., 1983), suggesting a close relationship between anatomical site and virus type in monkeys
and in humans. Resza et al. (1991) have isolated a second
papillomavirus from colobus monkeys, which transforms
established cells with the same frequency as BPV-1;
it is not known whether this virus can transform
primary cells.
In all papillomaviruses, the early region of the viral
genome is responsible for transformation; however,
recently it has become clear that the late region too can
play a significant role. The whole late region of BPV-1
can be deleted without appreciable loss of transformation efficiency, at least in established cells (Lowy et al.,
1980; Campo & Spandidos, 1983), whereas Meyers &
Wettstein (1991) have shown that the CRPV genome
possesses an element within the 3' end of the L1 open
reading frame (ORF) which is required for transformation of rabbit keratinocytes; another element within the
5' end of the L2 ORF inhibits NIH 3T3 transformation
(Table 2).
Perhaps the most peculiar in its transformation
behaviour is BPV-4; its genome is required for induction
of the transformed state both in vivo and in vitro, but is
not present either in frank cancers or in fully transformed
cells, indicating that additional events play an important
role in progression and maintenance of the neoplastic
Table 4. Oncogenes of papillomaviruses
BPV-1
BPV-4
CRPV
HPV-16
HPV-8
E5
E6
E7
E8
+*
?+
-
+
+
+
+
-*
+
+
+
-
?+ *
-
* Symbols: + , indicates recognized oncogenes; - , indicates either
non-transforming or absent O R F s ; ?, indicates uncertain O R F
functions. See text for details.
state (Campo et al., 1985; Smith & Campo, 1989) (Table
3). Accordingly, in naturally occurrring cancers the
cellular ras gene is activated and occasionally amplified
(Campo et al., 1990); in cells transformed in vitro BPV-4
induces the amplification of cellular sequences highly
homologous to the so-called autonomously replicating
sequences (ARSs) (K. T. Smith, L. W. Coggins, I.
Doherty, W. D. Pennie & M. S. Campo, unpublished
results) which have been shown to be involved in D N A
amplification (Grummt, 1989). These amplified sequences are capable of transient autonomous replication
(K. T. Smith, L. W. Coggins, I. Doherty, W. D. Pennie &
M. S. Campo, unpublished results) and we postulate that
BPV-4-induced amplification of ARSs may lead to
amplification and activation of neighbouring oncogenes.
That the loss of BPV-4 DNA in transformed cells is
not an in vitro artefact has been proved in the nude mouse
xenograft system, a technique pioneered by Kreider et al.
(1986). We have recently reported the spontaneous
malignant progression of one of 57 BPV-4-induced
papillomatous cysts in the nude mouse renal capsule
(Gaukroger et al., 1991). Viral D N A was detected only in
the papilloma fronds but not in the cancer and
metastases, in agreement with our previous findings
(Campo et al., 1985). We are expanding this work, to
mimic the cooperation between BPV-4 and chemical
carcinogens as observed in the field. Treatment of the
nude mice with either the tumour promoter 12-0tetradecanoylphorbol-13-acetate or the initiator dimethylbenzanthracene dramatically increased the progression rate, with six of 12 and 14 of 20 cases respectively
progressing to malignancy. Again no viral D N A was
found in those cancers tested (J. Gaukroger et al.,
unpublished results). These results confirm the synergism between viral and chemical carcinogens, and
suggest that BPV-4 can cooperate with either an initiator
or a promoter substance. We are currently investigating
in the same experimental system the synergism between
BPV-4 and quercetin, a mutagen present in bracken fern
which may be the environmental co-carcinogen in
oncogenesis in cattle (Jarrett et al., 1978; Campo &
Jarrett, 1987).
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Review: Transformation by papillomaviruses
Table 5. E7 protein
HPV-16
BPV-4
CRPV
BPV-1
HPV-8
219
Table 6. E6 protein
Rb
CKII
Zn
+*
+
-
+
-*
-
+
+
+
+
+
Transformation
+
+
+
-
* Symbols: +, indicates presence of domain and transformation
potential; - , indicatesabsenceof domainand transformationability.
As a rule, papillomaviruses have two oncogenes which
can cooperate in transformation (Table 4). Thus the
oncogenes of BPV-1 are E5 and E6 (Schiller et al., 1984,
1986; Yang et al., 1985; Schlegel et al., 1986); of HPV-16,
E6 and E7 (Munger et al., 1989a; Watanabe et al., 1989);
and of BPV-4, E7 and possibly E8 (Jaggar et al., 1990;
Jackson et al., 1991). E6 is the major transforming gene
of CRPV in in vitro assays in which E7 contributes less
(Meyers & Wettstein, 1991), but E7 is essential for
tumour formation in vivo (Brandsma et al., 1991), thus
providing functions that E6 lacks. Conversely the only
oncogene of HPV-8 seems to be E6 (Iftner et al., 1990).
Several domains have been identified in HPV-16 E7
by various laboratories (Dyson et al., 1989; Munger et al.,
1989b; Barbosa et al., 1990): the p105 retinoblastoma
gene product (Rb)-binding domain, the casein kinase II
(CKII) phosphorylation sites, and the two zinc-binding
Cys-x-x-Cys motifs (Table 5). The transformation properties of HPV-16 E7 depend primarily on Rb-binding
and zinc-binding; mutations in either of these two
domains abolish transformation (Edmonds & Vousden,
1989; Chesters et al., 1990), highlighting their critical
role. Binding of E7 to p 105Rb prevents the interaction of
the latter with its natural targets (Defeo-Jones et al.,
1991; Rustgi et al., 1991); the zinc fingers are essential
for the trans-activation activity of E7 (Phelps et al., 1988)
and mutations that disrupt them destabilize the protein
(Storey et al., 1990). The CKII sites, although less critical
(Watanabe et al., 1990; Storey et al., 1990), nevertheless
contribute to the transforming activity of HPV-16 E7
(Barbosa et al., 1990; Firzlaff et al., 1991). BPV-4 E7
does not have serine residues at positions 31 and 32,
which are phosphorylated in HPV-16 E7, but has the
necessary p l05Rb-binding domains (Jaggar et al., 1990;
Jackson et al., 1991). Given that continued expression of
BPV-4 is not necessary for the maintenance of the
transformed state (Campo et al., 1985; Jaggar et al.,
1990), it is reasonable to postulate that either binding of
pl05Rb by BPV-4 ET, albeit transient, is crucial or the
protein has yet another function. The E7 proteins of
BPV-1 and HPV-8 do not have either the Rb-binding site
or the CKII site (Iftner et al., 1990) and are not
BPV-1
HPV-16
BPV-4
Transcriptional activator.
Complex with p53; transcriptionalactivator.
Missing.
transforming (Iftner et al., 1988). Instead they are
involved in the regulation of DNA copy number, as
shown by Lusky & Botchan (1985) and Iftner et al.
(1988), respectively. CRPV E7 also lacks the CKII
domain (Barbosa & Wettstein, 1988) but, as stated
above, is nonetheless necessary for full malignant
transformation in vivo (Brandsma et al., 1991).
E6 is the second major oncogene of both BPV-1 and
HPV- 16 (Schiller et al., 1984; Yang et al., 1985; Munger
et al., 1989a; Watanabe et al., 1989). Like E7, E6 binds
zinc through Cys-x-x-Cys repeats (Barbosa et al., 1989).
BPV-1 E6 is a probable transcriptional activator
(Lamberti et al., 1990), which may contribute to cell
transformation by altering the transcriptional programme of critical cellular genes. In addition to being a
potential transcriptional activator (Lamberti et al., 1990;
Sedman et al., 1991), HPV-16 E6 binds another negative
regulator of the celt cycle, p53, promoting its degradation
through the ubiquitin pathway (Werness et al., 1990;
Scheffner et al., 1990), and therefore sequestering it from
controlling cell proliferation.
The E6 ORF is present in all the papillomaviruses
sequenced so far, with the notable exception of the
epithelial BPVs (Table 6) (Jackson et al., 1991). These
viruses all lack an E6 ORF. They are low in sequence
similarity over the area where the E6 ORF ought to be,
while displaying a high degree of relatedness throughout
the rest of their genomes.
In these BPVs, further 5' to the E7 ORF, there is the
small E8 ORF which encodes a peptide very similar to
E5, the major oncoprotein of BPV-1. The E8 peptide is
highly hydrophobic and theoretically capable of forming
a transmembrane a-helix, similar to the one postulated
for E5 (Fig. 1). However, critical amino acids, which
have been shown to be necessary for transformation
(Horwitz et al., 1988, 1989), are either missing, such as
the two terminal Cys residues, or are different in E8.
Moreover, E5 transforms cells in vitro (Schiller et al.,
1986) but E8 does not, and its overexpression in the
absence of other BPV-4 genes is lethal (Jaggar et al.,
1990; W. D. Pennie & M. S. Campo, unpublished
results). In vivo, E8 is expressed in the deep layers of
alimentary papillomas, where little or no vegetative viral
DNA replication takes place (R. Anderson & M. S.
Campo, unpublished results) and can therefore be
considered a true 'early' protein; in in vitro transient
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220
M . S. Campo
BPV-I
E5
BPV-4
E8
Fig. 1. Putative transmembrane configuration of BPV-1 E5 and BPV4 E8. The C terminus of BPV-1 E5 faces the extraceUular space and the
lumen of the ER and Golgi apparatus vesicles (Burkhardt et al., 1989);
BPV-4 E8 has been similarly oriented, although its configuration
remains to be proved. The amino acids of BPV-1 E5 that have been
shown to be critical for cell transformation (Horwitz et al., 1988, 1989)
are shaded.
expression assays, it is found mostly localized in
membranes and the Golgi apparatus and to a lesser
degree in the plasma membrane (W. D. Pennie & M. S.
Campo, unpublished results), similar to BPV-1 E5
(Burkhardt et al., 1989).
BPV-1 E5 has been shown to activate EGF, PDGF
and other membrane receptors (Martin et al., 1989; Petti
et al., 1991), and to bind a 16K cellular protein
(Goldstein & Schlegel, 1990), recently identified as the
16K component of gap junctions and of the vacuolar
proton channel-forming ATPase (Goldstein et al., 1991),
involved both in cell-cell communication and in intracellular traffic (Leitch & Finbow, 1990; Finbow et al.,
1991). The activation of several membrane receptors by
E5 can be ascribed, at least in part, to the E5-16K
complex: the resulting malfunction or disruption of the
16K functions involved in acidification of endosomal
vesicles would lead to prolonged ligand-receptor interactions, receptor activation and cell transformation
(Goldstein et al., 1991; Finbow et al., 1991). Alternatively, or in addition, E5 may bind the gap junctional
form of 16K, interfering with cell-cell communication
and releasing the cell expressing E5 from the control
exerted by neighbouring normal cells, thus contributing
to cell transformation. Both BPV-1- and BPV-4-transformed cells lack junctional communication (W. D.
Pennie, J. Pitts & M. S. Campo, unpublished results)
and we ascribe this effect to the binding of E5 and E8
respectively to 16K, although this awaits formal experimental proof.
Recently attention has been focused on the activity of
the E 5 0 R F of several HPVs. Since Chen & Mounts
(1990) showed that E5 of HPV-6 can transform
established cells, a search for a common mechanism of
transformation by the different E5 proteins has revealed
that HPV-16 E5, like BPV-1 E5, can activate EGF
receptors (Pim et al., 1992) and phosphatidylinositol 3'
kinase (R. McGlennen & R. Ostrow, personal communication). Furthermore, primary cervical keratinocytes
harbouring HPV-16 sequences do not have functional
gap junctions, as already observed for BPV-4- and BPV1-transformed cells (J. Pitts, G. M. McGarvie, G.
Sibbett & M. S. Campo, unpublished results).
It is clear that, despite their similar genetic plan and
overall homology, papillomaviruses use different strategies to achieve their common goals. Continuous viral
gene expression appears to be mandatory for the
maintenance of the neoplastic state in some cases, but
not in others; the same protein can have two different
roles in two different viruses, or be absent in a third, and
it is not inconceivable that a protein may have two
different functions in two different cell types, although
this has yet to be established.
The results obtained in animal systems have paved the
way for research on HPVs and the part they play in cell
transformation. Some questions, such as the role of the
immune system in virus control and tumour regression,
and the usefulness of antiviral or anti-tumour vaccines,
can only be addressed in animal systems. Only in animals
can the immune response be studied following experimental infection and vaccination of the natural host
(Jarrett et al., 1991; Christensen et al., 1991).
I wish to thank all those colleagues who shared with me their latest
and unpublished results, and my own collaborators who have greatly
contributed to the work presented in this review. I am grateful to Drs
Maria Jackson and John Wyke for their critical reading of the
manuscript. The contents of this review were first presented as a lecture
at the 1991 International Papillomavirus Worshop held in Seattle, July
20 to 26. I acknowledge the continuous financial support of the Cancer
Research Campaign, of which I am a Fellow.
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