Cellular Oncogenes

Oncogenes (tumor-causing genes) were originally
identified in RNA tumor viruses (retroviruses)
as genes (v-onc) that could transform
cells into an altered state of control of cell proliferation,
often resulting in a tumor, mainly in
chicken, mice, and rats. More than 20 different
viral oncogenes are known to have a counterpart
in normal cells (c-onc), called proto-oncogenes
or cellular oncogenes. These cellular
genes are highly conserved in evolution because
they have important functions in all
eukaryotic cells. They encode proteins that are
required at defined sites throughout the cell
where they regulate the ordered progression
through the cell cycle, cell division, and differentiation.

Cellular and viral oncogenes

A typical retrovirus contains an RNA genome
that codes for three genes or groups of genes:
gag (group-specific antigen), pol (polymerase),
and env (coat protein, envelope). As with all
genes of higher organisms, a cellular oncogene
(c-onc) consists of exons and introns with defined
structure and sequence, as in the gene src
(the name is derived from sarcoma, a tumor
that is induced by a change in this gene). The
virus may contain parts of the cellular oncogene
(c-scr). This is designated viral oncogene (v-src)
(Rous sarcoma virus). In chickens, it induces a
malignant tumor (a sarcoma), first observed by
Peyton Rous in 1911. Since many cellular oncogenes
are also known in an altered, viral form, it
is assumed that the viruses have integrated
parts of the respective cellular oncogenes into
their own genomes.

Virus-induced tumors

Virus-induced tumors are known especially in
chickens, rodents, and cats. In man, they do not
play a general role in the induction of tumors.
Important exceptions are papilloma virus-induced
carcinoma of the cervix and carcinoma of
the liver secondary to hepatitis virus infection.

Mechanisms of oncogene activation

A cellular oncogene controls cell division. It
controls the time and location of the orderly
proliferation of cells and tissues (normal
growth). Genetic changes can lead to disorders
of the regulation of cell divison, increased proliferation
of cells, and formation of a tumor. This
can be traced back to relatively few mechanisms.
A point mutation in a critical region of
the gene can lead to disturbances in the regulation
of cell division. Examples are mutations in
codon 12 or 63 or the H-ras gene.
An inactive cellular oncogene may become activated
when it is moved by chromosomal translocation
to the vicinity of an active gene. In
Burkitt lymphoma, an inactive gene is moved to
the region of an active gene for the H or L chain
of an immunoglobulin. In other cases, the
breakpoint of the chromosome translocation
may lie within a cellular oncogene and thereby
affect its expression. An example is the
Philadelphia translocation (see p. 332). Multiplication
(amplification) of a gene is a futher
mechanism that can lead to altered (usually increased)
expression.

Examples of cellular oncogenes and their proteins

The table shows examples of the about 60
known cellular oncogenes, their basic functions,
a fewtumors induced inman by mutation
of the cellular oncogene (c-onc), and tumors induced
in vertebrates by the homologous viral
onogene (v-onc).

The p53 Protein, a Guardian of the Genome

The p53 protein (named after its molecular
weight of 53 kD), a nuclear phosphoprotein, is
indispensable for genomic integrity and cell
cycle control. It binds to specific DNA sequences
and regulates the expression of different regulatory
genes involved in growth. It interacts
with other proteins in response to DNA damage
and mediates apoptosis (cell death) of the cell
when the damage is beyond repair. Its basic
function is to control entry of the cell into the S
phase (see cell cycle control, p. 112). Somatic
mutations in the p53 gene occur in about half of
all tumors. Germline mutations lead to a familial
form of multiple different cancers

The human p53 protein

The active form of the human p53 protein is a
tetramer of four identical subunits. Each subunit
has 393 amino acids and five highly conserved
regions, I–V. Region I is part of the transcription-
activation domain; regions II–V
belong to sequence-specific DNA-binding
domains. The carboxyl end beyond amino acid
300 consists of a nonspecific DNA interaction
domain and the tetramerization domain. Proteins
encoded by DNA tumor viruses bind to
p53 and inhibit its activity.Mutations in the p53
gene on human chromosome 17 at p13 (spanning
20 kb of DNA and yielding a 2.8 kb mRNA
transcript from 11 exons) have the greatest effect
when they occur in the conserved regions
II–V in codons 129–146 (exon 4), 171–179
(exon 5), 234–260 (exon 7), and 270–287 (exon
8). Particularly vulnerable are the conserved
amino acids arginine (R) in positions 175, 248,
249, 273, and 282 and glycine (G) in position
245. Mutations occur mainly as missense, resulting
from base-pair substitutions, but some
are insertions and deletions and exert a dominant
negative effect. Knockout mice develop
normally, but develop tumors at a high rate. Activated
benzopyrene induces mutations at codons
175, 248, and 275 in cultured bronchial
epithelial cells.