PART ONE
General Cytology
HR E6 proteins: disturbance of apoptosis and cellular
scaffolding
• Degradation of apoptosis promoting cellular proteins (p53, Bak)
• Alteration of cell polarity, differentiation and senescence by binding
to scaffold protein of the cell (PDZ domain proteins)
Induction of telomerase (hTERT)
Interference with the mitotic spindle apparatus and induction of
chromosomal alterations
HR E7 proteins: unrestricted cell cycle progression and
proliferation
Induction of proliferation by inactivation of Gl/S-phase arrest
- Release of E2F transcription factors by interaction with pocket
proteins (pRB, p107, p130) (binding to pRB specific for HR E71)
and
- Abrogation of CDK-inhibitors p21 and p27
- Stabilization of cyclin A and D
Induction of additional centrosomes, aberrations of mitosis
Interference with immune responses by inhibiting interferon
response genes
Fig. 1.15 Interactions with cellular
proteins and oncogenic functions
of the
HR-HPV proteins E6 and E7.
restriction to the transformation zone of the uterine cervix.
Although HR-HPV infection occurs at multiple sites in the male
and female anogenital tract, the epithelial cells of the trans-
formation zone of the cervix appear to be substantially more
sensitive to HPV-mediated transformation than other HPV-
infected epithelial cells in the vagina, vulva, outer surface of the
cervix, and particularly the epithelium of the penis, which only
rarely become transformed. These peculiar epidemiological
features point out important molecular differences in these dif-
ferent host cells. It is very likely that these differences rely on the
stringency of the molecular control that prevents the activation
of the E6 and E7 oncogenes in the basal cells of the epithelium.
Given the fact that the molecular features that mediate this con-
trol are an inherent part of the differentiation control system of
the epithelial cells, it can be speculated that the need for epithe-
lial stem cells at the transformation zone of the uterine cervix
plays an important role. Stem cells of the transformation zone
retain two potential pathways: to differentiate under the influ-
ence of high estrogen levels into a single-layer glandular epithe-
lium, and to differentiate under the influence of low estrogen
levels into a multilayer squamous epithelium. These morpho-
logical differences are regulated by the activation of different sets
of genes and hence different epigenetic regulatory mechanisms
that become activated in either situation. There is accumulating
evidence that these epigenetic control mechanisms are also used
by the papillomavirus genome to either restrict or activate the
expression of their genes. The multipolar differentiation capac-
ity of the epithelial cells at the uterine transformation zone may
thus explain why these cells are so much more sensitive to trans-
formation by HR-HPV types than many other infected cells of
the human body.
Once the activation of the viral oncogenes in the basal cells of
the infected epithelium has occurred and the first transformed
cells that display chromosomal instability have expanded, the
lesions may progress from a CIN 1 lesion (representing acute
replicating HPV infections) to CIN 2 and 3 lesions (reflecting
transforming HPV infections) and finally invasive carcinomas
(Fig. 1.14).
The knowledge now gathered on this important step of the
HPV-associated transformation process offers new targets for
screening and diagnosis of cervical precancer and cancer. Acti-
vation of the expression of the HR-HPV E6 and E7 genes in the
basal and parabasal cells results in overexpression of a cellular
protein, p16INK4a.31-35 All cells that express HR-HPV proteins
and retain the capacity to proliferate express extremely high lev-
els of the p16INK4a protein; hence p16INK4a is an interesting
surrogate marker for HPV transformed cells.
Based on these findings it can be expected that in the near
future these new techniques will have a deep impact on revised
cervical cancer screening programs.
Research over the past thirty years has thus made it pos-
sible to identify an infectious agent (HR-HPV) as cause of
a major human cancer. The experimental analysis as well as
epidemiological research has made it possible to clarify the
role of these viruses in carcinogenesis. Detailed analysis of
the expression and function of viral genes has revealed that
it is not the acute infection by HPVs but rather the lack of
normal cellular control functions that suppress their expres-
sion in basal cells that initiates the transforming infection
and may result finally in full neoplastic transformation of
individual infected cells. This research has paved the way
for substantially improved diagnostic and therapeutic tools,
including novel assays for cervical cancer screening as well
as major global vaccination programs that aim to prevent
the primary infection of humans by HPV and were shown to
effectively prevent induction of HPV-induced preneoplastic
or neoplastic lesions.
Concluding Remarks
The scientific analysis of cells and their components as the
essential units of complex organisms has initiated a dramatic
development in biomedical research and finally led to the
identification of the essential biochemical basis of inherit-
ance and diversity of life. It has initiated a paradigm shift
in biology from a purely descriptive science to one that has
made it possible to fully explore the construction kits of life.
Genes have been recognized as the basic units of inherit-
ance and their activity in given cells has been realized as the
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