Beyond loss of suppression gainoffunction effects

The paradigm of tumor suppressor genes implies that mutation results in inactivation, is accompanied by loss of the other allele, and the protein altogether disappears from cancer cells. With TP53, however, many missense mutations have a stabilizing effect and lead to the accumulation of mutant protein in the nucleus of cancer cells, sometimes in the presence of the remaining wildtype allele. This specificity has allowed the use of immunohistochemistry to detect ''mutant'' p53 in cancer tissues. While there is a fairly good correlation between missense mutation and protein accumulation, many mutations do not result in protein accumulation (e.g nonsense mutations, insertions and deletions) and wild-type p53 may accumulate in response to stress. Thus, care should be exercised in the use of immunohisto-chemistry as a surrogate for mutation analysis. The presence of high levels of mutant p53 and the frequent retention of a wild-type allele in cancer cells, has led to speculation that mutant p53 may exert dominant effects in carcinogenesis

(de Vries et al., 2002). Indeed, mutant p53 complexes with wild-type and inactivates its suppressor functions (dominant-negative effect). There is also some evidence that mutant p53 may behave as an independent, oncogenic protein. The molecular basis of this activity is not known, but the recent finding that mutant p53 can bind to and inactivate some p63 and p73 isoforms has led to the hypothesis that mutant p53 may also abrogate the suppressor functions of the other members of the family. This interaction might be dependent upon the polymorphism status at codon 72 of the TP53 allele which contains the mutation (Bergamaschi et al., 2003; Marin et al., 2000).

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