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Taken
together, these data made it possible to define the
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p53 gene as a
tumor suppressor gene. Yet unlike the Rb
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gene, which is
the archetype of the tumor suppressor
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genes, the p53
gene has some original features. In
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particular,
more than 95 % of alterations in the p53 gene
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are point
mutations that produce a mutant protein, which
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in all cases
has lost its transactivational activity (see
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above).
Nevertheless, the synthesis of these mutant p53
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proteins is
not harmless for the cell. In paticular, it has
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been shown
that some p53 mutants (depending on the
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site of
mutation) exhibit a transdominant phenotype and
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are able to
associate with wild-type p53 (expressed by the
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remaining
wild-type allele) to induce the formation of an
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inactive
heteroligomer (Milner and Medcalf 1991).
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Moreover,
cotransfection of mutant p53 with an activated
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ras gene shows
that some p53 mutants have high,
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dominant
oncogenic activity (Halevy et al. 1990). These
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observations
led to the proposal that several classes of
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mutant p53
exist, according to the site of mutation and its
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phenotype
(Michalovitz et al. 1991): i) null mutations with
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totally
inactive p53 that do not directly intervene in
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transformation;
ii) dominant negative mutations with a
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totally
inactive p53 that is still able to interfere with wild-
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type p53
expressed from the wild-type allele, and iii)
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positive
dominant mutations where the normal function
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of p53 is
altered but in this case the mutant p53 acquires
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an oncogenic
activity that is directly involved in
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transformation.
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