Physical and functional interaction between p53 mutants and different isoforms of p73

p53 is the most frequently inactivated tumor suppressor gene in human cance r, whereas its homologue, p73, is rarely mutated. Similarly to p53, p73 can promote growth arrest or apoptosis when overexpressed in certain p53-null tumor cells. It has previously been shown that some human tumor-derived p53 mutants can exert gain of function activity. The molecular mechanism under lying this activity remains to be elucidated. We show here that human tumor -derived p53 mutants (p53His175 and p53Gly281) associate in vitro and in vi vo with p73 alpha, beta, gamma, and delta. This association occurs under ph ysiological conditions, as verified in T47D and SKBR3 breast cancer cell li nes. The core domain of mutant p53 is sufficient for the association with p 73, whereas both the specific DNA binding and the oligomerization domains o f p73 are required for the association with mutant p53. Furthermore, p53His 175 and p53Gly281 mutants markedly reduce the transcriptional activity of t he various isoforms of p73. Thus, human tumor-derived p53 mutants can assoc iate with p73 not only physically but also functionally. These findings def ine a network involving mutant p53 and the various spliced isoforms of p73 that may confer upon tumor cells a selective survival advantage.