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with wild-type (wI) p53 proved the opposite. From these studies wt p53 was found to be
involved in growth suppression and inhibition of transformation (Finlay et aI., 1989; Eliyahu
et aI., 1989; Baker et aI., 1990). Therefore, the wt p53 gene has clear characteristics of a
tumor suppressor gene.
Different mechanisms have been found in human tumors that alter p53 and in turn
inactivate wt p53 function. These alterations can occur at either the protein or DNA level.
At the protein level, the wt p53 protein was found in a complex with various DNA tumor
virus encoded oncoproteins (EIB, large T antigen and E6). In addition, p53 was found in a
complex with MDM2, a cellular protein with transforming properties (Momand et aI., 1992).
Furthermore, mutant p53 can bind with wt p53 (see below). The binding of these proteins
most likely inactivates p53 and thereby contributes to oncogenesis. Alterations at the DNA
level appear to be the most common mechanism. These alterations include the presence of
a mutations in the p53 gene and loss of the chromosomal region that bears this gene. Most
tumors show a mutation in one copy of the gene and loss of the second allele because the p53
containing portion of chromosome 17p is lost. In these cases p53 follows a recessive
mechanism of tumorigenesis. Mutation analyses of the p53 gene in human tumors revealed
two remarkable findings. First, mutations in this gene were the most common genetic
alteration yet identified in human cancer. These include cancers of the colon, lung,
oesophagus, breast, liver, brain and hemopoietic tissues (Hollstein et aI., 1991; Levine et aI.,
1991; Levine, 1992). Second, 80% of p53 mutations involve single base changes (missense
mutations). Most mutations are clustered in the central, highly conserved regions of the gene.
However, the types and sites of the mutations can vary amoung tumor types and probably
reflect exposure to specific etiologic agents (Harris and Hollstein, 1993). Many of the p53
missense mutations, which lead to an amino acid change and a full-length mutant protein,
show similar detrimental effects on protein conformation (Gannon et aI., 1990) and function
(Kern et aI., 1992; Vogelstein and Kinzler., 1992). On the protein level an increase in halflife
from minutes to hours has been observed (Bartek et aI., 1991). Although most tumors
show abnormalities of both alleles, some tumors show only one mutated copy. This indicates
that in these cases p53 did not follow a recessive mechanism of tumor development. Instead
a 'dominant negative' mechanism was proposed in which only one mutated copy of p53 is
sufficient to contribute to tumor formation. One plausible explanation for this might be that
the abundantly expressed mutated p53 protein competes with and blocks the activity of the
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