PRINCIPLES OF TOXICOLOGY

284 CHEMICAL CARCINOGENESIS
TABLE 13.7 Tumor Suppressor Genes in Human Cancer and Genetic Disease
Gene Consequence of loss Function of encoded protein
Rb Retinoblastoma and osteosarcoma Binds and sequesters the transcription factor
E2F to maintain cells in G0 of cell cycle
p53 Li-Fraumeni syndrome inactivated in Transcription factor with multiple functions,
>50% of human cancers
including cell cycle progression, detection of
DNA damage, and apoptosis
p16 Familial melanoma, pancreatic cancer Inhibits CDK4 to block cell cycle progression
Wt1 Wilms’ tumor/nephroblastoma Transcription factor required for renal
development
VHL Von Hippel–Lindau syndrome renal cell Negative regulation of hypoxia-inducible
carcinoma
mRNAs
NF1 Neurofibromatosis type 1 schwannoma and GTPase-activating protein (GAP), which
glioma
regulates signaling through ras
NF2 Neurofibromatosis type 2 acoustic nerve Connects cell membrane proteins with the
tumors and meningiomas
cytoskeleton
BRCA1 Familial and sporadic breast and ovarian
cancer, also prostate and colon cancers
Secreted growth factor
BRCA2 Breast cancer (female and male) also prostate
cancer
Unknown function
DCC Colon cancer Cell adhesion molecule
APC Familial and sporadic adenomatous polyposis Interacts with catenins, proteins involved in
colorectal tumors
signaling pathway for tissue differentiation
MMR Hereditary nonpolyposis colorectal cancer Mediates DNA mismatch repair
gene (Rb) and the discovery that both copies of the gene are inactivated and/or deleted in retinoblastoma
tumors. It is now known that a large proportion of persons with retinoblastoma have inherited a
defective copy of the Rb gene. Tumors develop when the second copy is inactivated prior to the terminal
differentiation of the retinoblasts. Another group of retinoblastoma patients do not have a defective
copy of the Rb gene. In this group, two somatic mutations have occurred sometime after conception.
Individuals born with a mutated copy of Rb gene are also at a higher risk of developing other cancers,
most notably osteosarcoma, later in life. A number of the known or putative tumor suppressor genes
appear to be involved in a relatively small subset of tumors specific to certain tissue types. These include
Wt-1 (Wilms’ tumor), NF-1 and NF-2 (neurofibromatosis types 1 and 2), APC (adenomatous polyposis
coli), and DCC (deleted in colon carcinoma). In contrast to these, the p53 tumor suppressor gene, is
inactivated in more than 50 percent of all human tumors. The p53 protein is a remarkable protein that
is involved in diverse cell functions including the detection of DNA damage, the regulation of cell
cycle progression, and the induction of apoptosis or programmed cell death. Rb and p53 will be
discussed briefly below as well as in the context of the cellular functions in which they are involved.
The p53 gene and the protein it encodes has been called the “guardian of the genome” in recognition
of the critical role it plays in the life and death of cells. The p53 gene is considered to be the most
frequently mutated gene in human tumors. Approximately 40 percent of breast cancers, 70 percent of
colon cancers, and 100 percent of small cell lung cancers contain mutations in the p53 gene. The p53
gene encodes a 53-kD nuclear phosoprotein that is active in regulating the transcription of a number
of genes relating to cell cycle progression and apoptosis. Levels of p53 are increased in response to
several types of cell stress, including DNA damage, hypoxia, and decreases in the levels of nucleotide
triphosphates required for DNA replication. The p53 protein has been shown to have a direct role in
the detection of DNA damage by some chemical carcinogens and radiation. In the presence of DNA
damage p53 has the ability to slow cell cycle progression or bring the cycle to a halt until the damage
can be repaired. In the face irreparable damage p53 has been shown to initiate the events leading to
apoptosis.