Induction of gene amplification as a gain-of-function phenotype of mutant p53 proteins

Sally El-Hizawi, James P. Lagowski, Molly Kulesz-Martin, Amador Albor

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47 Scopus citations


Gene amplification accompanies tumor progression and is involved in the development of drug resistance. Previously, we reported (A. Albor et al., Cancer Res. 58: 2091-2094, 1998) that mutant p53 proteins conserve the capacity to interact with and activate topoisomerase I, and that this could be a mechanism for induction of genomic instability by mutant p53 proteins. To test this hypothesis, the effect of exogenous mutant p53 protein expression on genomic instability in human p53-/- Saos-2 cells was measured by the frequency of formation of N-(phosphoacetyl)-L-aspartate (PALA)-resistant (PALAR) colonies, mediated by gene amplification. Interaction of exogenous mutant p53 and topoisomerase I was confirmed by immunoprecipitation. Growth under continuous expression of mutant p53 proteins for 16-17 population doublings increased the frequency of appearance of PALAR colonies after subsequent exposure to PALA. Subtoxic concentrations of camptothecin (which stabilizes topoisomerase I cleavage complexes, mediating nonhomologous recombination) produced a dose-dependent increase in PALAR colonies, and combining expression of mutant p53 with exposure to camptothecin produced a greater than additive increase in PALAR colony formation. These results indicate that mutant p53 proteins promote gene amplification independently of their capacity to inactivate the wild-type p53 protein, and suggest that this effect is dependent on interaction of mutant p53 with topoisomerase I. Additional studies are needed to assess the potential of targeting mutant p53 interaction with topoisomerase I for the reduction of drug resistance development during chemotherapy.

Original languageEnglish (US)
Pages (from-to)3264-3270
Number of pages7
JournalCancer Research
Issue number11
StatePublished - Jun 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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