section 26.6
Regulation of Cell Proliferation: Oncogenes
611
TABLE 26-6
Some Oncogenes Involved in Human Cancers
*
Oncogene
Protein**
Cancer**
K-ras
p21 GTPase
pancreas, lung, colorectal
N-ras
p21 GTPase
endometrial, other carcinomas
H-ras
p21 GTPase
bladder
erb-B
EGF receptor
gliomas, carcinomas
erb-B2
growth factor receptor
breast, ovarian, gastric
C-myc
transcription factor
Burkitt’s lymphoma, SCLC
N-myc
transcription factor
neuroblastoma, SCLC
L-myc
transcription factor
SCLC
bcl
- 2
antiapoptosis protein
B-cell lymphoma
cycd
- 1
cyclin-D
B-cell lymphoma, carcinomas
bcr-abl
tryosine kinase
ALL (T cell), CML
cdk-4
cyclin-dependent kinase
sarcoma
/3-cat
transcription factor
melanoma, colorectal
hst
growth factor
gastric
mdm
- 2
p53 binding protein
sarcoma
gll
transcription factor
glioma, sarcoma
ttg
transcription factor
ALL (T cell)
*Each oncogene must be activated by a mutation. Most are activated by one or more somatic mutations. Germ line mutations that activate oncogenes
lead to familial cancers.
** Abbreviations: EGF, epidermal growth factor; SCLC, small cell lung carcinoma; ALL, acute lymphocytic leukemia; CML, chronic myelogen-
ous leukemia.
chimeric proteins are characterized by elevated protein
kinase activity.
If oncogenes are altered forms (or aberrantly expressed
forms) of normal genes that usually participate in growth
regulation, the number of different oncogenes should be
fairly small. Thus, we should expect that if a large number
of tumor viruses and tumors are screened for oncogenes,
the same ones should appear repeatedly. This is indeed
the case. For example, the oncogene in human bladder
carcinoma
(ras)
has been found in human lung and colon
carcinomas and in rat mammary carcinoma. A similar se-
quence but with a different base change was found in a
human neuroblastoma and a fibrosarcoma. This variant
was called
N-ras.
How oncogenes cause cellular transformation is un-
known. However, when a tumor virus brings into a cell an
oncogene whose sequence differs from the cellular proto-
oncogene, the mutant gene product probably causes trans-
formation because it is able to carry out some process
that the proto-oncogene fails to do. That is, the proto-
oncogene itself carries out a normal function or is silent;
only a mutation or chromosomal rearrangement produces
the cancerous cell.
Certain biological functions are not determined simply
by the presence of a particular gene product but by its
concentration. Thus, the conversion of a proto-oncogene
to an active oncogene may occur simply by changes in
concentration. The activity of a gene can be changed by
altering the adjacent promoter or regulatory sequences (or
both). Some oncogenes differ from the normal counter-
parts in that base changes exist only in the promoter and
these changes presumably alter the rate of RNA synthesis.
Another important mechanism by which the expression
of a proto-oncogene can be altered is by moving the gene
to a new location, e.g., by relocating it next to a different
promoter, separating it from an adjacent regulatory ele-
ment, or placing it adjacent to an enhancer. Thus, when
the viral DNA is inserted into the chromosome of an in-
fected cell, the viral oncogene may be expressed at a much
greater rate than the proto-oncogene, which remains at its
normal location.
Whereas oncogenes are characterized by gain of func-
tion, another class of genes are characterized by loss
of function; these are the
tumor suppressor genes,
which are often involved in familial (inherited) cancers
(Table 26-7). The rare human cancer
retinoblastoma
pro-
vided the first significant insight into tumor suppressor
genes. Retinoblastoma affects about 1 in 20,000 children
who usually develop tumors in both eyes. Affected in-
dividuals have a small deletion in chromosome 13 that
