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endogenous wt p53 by forming mixed tetrameric complexes (Kern et aI., 1992; Harris et aI.,
1992; Hupp et aI., 1992). Reports have also appeared in which certain missense p53
mutations show some oncogenic properties as well (Wolf et aI., 1984; Dittmer et aI., 1993).
Thus, these missense p53 mutations can not only result in functional competition with wt p53
resulting in loss of function, but some of them have gained also new properties that result
in a gain of function.
Mutations in p53 were not only found in sporadic human cancers but also in the
germline of patients with the Li-Fraumeni cancer syndrome (Malkin et aI., 1990). These
patients are characterized by a high incidence of different cancers including early-onset breast
carcinoma, childhood sarcomas, and other neoplasms. However, other cancers, for example
colon and small cell lung carcinoma, with a high incidence of somatic mutations of pS3 are
hardly observed in Li-Fraumeni patients. This might be due to the capacity of a certain tissue
to divide once a mutation in 1'53 has occurred or is constitutionally present and thereby
increasing the chance of undergoing a second mutation in the gene. For instance breast tissue
displays an increased growth in adolescence, whereas colon and lung tissues have only a
limited potential to divide under normal conditions (Knudson, 1993). Germline mutations in
p53 are also, though very rarely, observed in childhood sarcomas (Toguchida et aI., 1992)
and among some women with breast cancer (Borresen et aI., 1992). Transgenic p53 knockout
mice (Donehower et aI., 1992) and mice expressing mutated p53 proteins (Lavigueur et
aI., 1989) showed that p53 is not important for embryonic development, because the mice
were viable and appeared completely normal, although they displayed an increased risk for
the development of some tumor types, particularly lymphomas.
Functional studies of the p53 protein have revealed that p53 plays a role in the control
of the cell cycle (Bischoffet aI., 1990; Stuzbecher et aI., 1990), processes involving DNA
repair, DNA replication, genomic instability (Kastan et aI., 1992; Yin et aI., 1992;
Livingstone et aI., 1992), and programmed cell death (Clarke et aI., 1993; Lowe et aI.,
1993a; Lowe et aI., 1993b). Although p53 occupies an important position in all the above
mentioned processes this protein is probably not required in normal cells. However, when
the cells are damaged, for instance by gamma-irradiation, the concentration of p53 increases.
This results in an arrest of the cell cycle, which allows the repair of DNA damage. Thus,
p53 is supposably acting as a kind of 'guardian of the genome' (Lane, 1992). The most likely
way by which p53 executes these various activities is through its ability to act as a
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