Page 376 - Review of Medical Microbiology and Immunology ( PDFDrive )

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365
CHAPTER 43 Tumor Viruses
(5) Certain cellular oncogenes isolated from normal
Involved in Human Cancer
cells can cause malignant transformation if they have been
modified to be overexpressed within the recipient cell.
Important Human Cancer
Tumor Suppressor Gene
In summary, two different mechanisms—mutation and
increased expression—appear to be able to activate the
Retinoblastoma; carcinoma of breast,
Rb
bladder, and lung
quiescent “proto-oncogene” into a functioning oncogene
capable of transforming a cell. Cellular oncogenes provide
astrocytoma
a rationale for carcinogenesis by chemicals and radiation
(e.g., a chemical carcinogen might act by enhancing the p53 Carcinoma of breast, colon, and lung;
WT1
Wilms’ tumor of kidney
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expression of a cellular oncogene). Furthermore, DNA iso-
DCC
Carcinoma of colon
lated from cells treated with a chemical carcinogen can
malignantly transform other normal cells. The resulting
tumor cells contain cellular oncogenes from the chemically
treated cells, and these genes are expressed with high
there are micro-RNAs that bind to (“silence”) mRNA tran-
efficiency.
scribed from a tumor suppressor gene. As a result, the
tumor suppressor protein is not synthesized, which
2. Role of Cellular Tumor Suppressor
enhances the likelihood of tumorigenesis.
Genes in Tumorigenesis
There is another mechanism of carcinogenesis involving
cellular genes, namely, mutation of a tumor suppressor
INFECTION
gene (Figure 43–1). A well-documented example is the reti- OUTCOME OF TUMOR VIRUS
The outcome of tumor virus infection is dependent on the
noblastoma susceptibility gene, which normally acts as a
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virus and the type of cell. Some tumor viruses go through
suppressor of retinoblastoma formation. When both alleles
their entire replicative cycle with the production of progeny
of this antioncogene are mutated (made nonfunctional),
retinoblastoma occurs. Human papillomavirus and SV40
gous to lysogeny, in which the proviral DNA is integrated
virus produce a protein that binds to and inactivates the
into cellular DNA and limited expression of proviral genes
protein encoded by the retinoblastoma gene. Human papil-
occurs. Therefore, malignant transformation does not
lomavirus also produces a protein that inactivates the pro-
require that progeny virus be produced. Rather, all that is
tein encoded by the p53 gene, another tumor suppressor
required is the expression of one or, at most, a few viral
gene in human cells. The p53 gene encodes a transcription
genes. Note, however, that some tumor viruses transform
factor that activates the synthesis of a second protein,
which blocks the cyclin-dependent kinases required for cell
a cellular oncogene.
division to occur. The p53 protein also promotes apoptosis
In most cases, the DNA tumor viruses such as the papo-
of cells that have sustained DNA damage or contain acti-
vaviruses transform only cells in which they do not repli-
vated cellular oncogenes. Apoptosis-induced death of these by inserting their proviral DNA in a manner that activates
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cate. These cells are called “nonpermissive” because they do
cells has a “tumor-suppressive” effect by killing those cells
not permit viral replication. Cells of the species from which
destined to become cancerous.
the DNA tumor virus was initially isolated are “permissive”
Inactivation of tumor suppressor genes appears likely to
be an important general mechanism of viral oncogenesis.
tumors are formed). For example, SV40 virus replicates in
Tumor suppressor genes are involved in the formation of
the cells of the African green monkey (its species of origin)
other cancers as well (e.g., breast and colon carcinomas
and causes a cytopathic effect but no tumors. However, in
and various sarcomas). For example, in many colon carci-
rodent cells, the virus does not replicate, expresses only its
nomas, two genes are inactivated, the p53 gene and the
early genes, and causes malignant transformation. In the
DCC (deleted in colon carcinoma) gene. Table 43–4 lists
several important tumor suppressor genes and their rela-
grated into the host chromosome and remains there
tionship to various human cancers. More than half of
through subsequent cell divisions. The underlying concept
human cancers have a mutated p53 gene in the DNA of
applicable to both DNA and RNA tumor viruses is that
malignant cells. “nonproductive” transformed cell, the viral DNA is inte-
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only viral gene expression, not replication of the viral
genome or production of progeny virus, is required for
3. Role of Cellular Micro-RNA Genes in
transformation.
Tumorigenesis
The essential step required for a DNA tumor virus (e.g.,
Micro-RNA genes do not encode proteins but rather exert
sion of the “early” genes of the virus (Table 43–5). (The
their regulatory effect by being transcribed into micro-
RNA that can bind to sequences in mRNA and prevent that
early genes are those expressed prior to the replication of
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