612
chapter 26
Regulation
of
Gene Expression
TABLE 26-7
Some Tumor Suppressor Genes Involved in Human Cancers
*
Tumor Suppressor Gene
Protein
Cancer
Rb-1
E2F1 binding
p53
transcription factor
p l
6
cyclin-dependent, kinase inhibitor
APC
regulates /3-catenin
MSH1, MLH2,
PMSI, PMS2
DNA mismatch repair
WT-1
transcription factor
NF-1
p21ras-GTPase
VHL
protein stability regulator
BRCA-1
?DNA repair
BRCA-2
DNA repair
PTEN
tyrosine phosphastase
DPC4
TGF-jS pathway
E-CAD
transmembrane cell-cell adhesion
molecule
DCC
transmembrane receptor
MEN-1
undetermined
retinoblastoma, osteosarcoma
Li-Fraumeni syndrome, -50% of all cancers
breast, lung, bladder, pancreas, -30% of all cancers
familial adenomatous polyposis
hereditary non-polyposis
colorectal cancer
Wilms’ tumor
melanoma, Neurofibromatosis type 1, neuroblastoma
renal (clear cell), von Hippel Lindau syndrome
ovarian, familial breast cancer
familial breast cancer, pancreas
breast, prostate, thyroid, glioma
pancreas
gastric, breast
colorectal, other carcinomas
parathyroid, adrenal, pituitary
*Mutations in tumor suppressor genes (many of which code for transcription factors) alter an essential cellular activity that regulates growth.
Mutations occur both in somatic cells and in germ line cell and are often the cause of hereditary cancers.
predisposes mutations to occur in the homologous chro-
mosome by mitotic recombination. Thus, in the majority
of cases of retinoblastoma, one mutation is transmitted in
the germline and the other arises as the result of a somatic
mutation.
It is estimated that 5-10% of breast cancers are due
to germline mutations in the cancer susceptibility genes
BRCA-1
and
BRCA-2,
which are also tumor suppressor
genes. Carriers of the
BRCA-1
mutation have an 80-90%
lifetime risk of developing breast cancer; carriers of the
BRCA-2
mutation have a lesser risk. Ashkenazi Jews and
the population of Iceland carry founder mutations since
only one mutation, or a very few mutations, occurs re-
peatedly in the
BRCA-1
and
BRCA-2
genes among breast
cancer patients in these populations. As a result, it is possi-
ble to genetically screen many individuals at high risk for
harboring particular alleles of the
BRCA-1
and
BRCA-2
genes.
However, even with extensive counseling, learning
that one is at high risk for developing breast cancer carries
a heavy emotional burden. The only medical intervention
offered at present for young, high-risk carriers of
BRCA-1
or
BRCA-2
genes is prophylactic mastectomy to avoid fu-
ture development of breast cancer.
Tumorigenesis is a complex, multistep process involv-
ing acquisition of a number of genetic lesions. Whereas
the mutations in oncogenes can cause unregulated growth,
a deletion or a mutation in
tumor suppressor genes
(also called
antioncogenes)
can also predispose nor-
mal cells to become cancer cells. Thus, induction of a
malignant phenotype involves a mutation in oncogenes,
tumor suppressor genes, and perhaps other genes. In
human colon cancer, defects in both oncogene and
tumor suppressor genes are known. The latter have been
assigned to chromosomes 5, 17, and 18.
26.7 Retroviruses and AIDS
Since
1980 three types of infectious
human
T-cell
lymphotrophic viruses
(HTLVs) have been identified.
HTLV-I is frequently associated with adult forms of
T-cell leukemia-lymphoma,
HTLV-II with
hairy T-cell
leukemia,
and HTLV-III (now called human immun-
odeficiency virus; HIV) with
acquired immunodefi-
ciency syndrome (AIDS).
Other related retroviruses
have been isolated from human and primate popula-
tions. Molecular biologists have developed a wealth of
information about the biology and genetics of retro-
viruses, including the complete sequencing of their
genomes. Despite this enormous research effort it still
