Disruption of the p53-Mdm2 complex by nutlin-3 reveals different cancer cell phenotypes

Nicoleta C. Arva, Kathryn E. Talbott, Danielle R. Okoro, Angelika Brekman, Wei Gang Qiu, Jill Bargonetti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Introduction: Mdm2 inhibits p53 transactivation by forming a p53-Mdm2 complex on chromatin. Upon DNA damage-induced complex disruption, such latent p53 can be activated, but in cells overexpressingMdm2 because of a homozygous single nucleotide polymorphism at position 309 (T→C) of mdm2, the complex is highly stable and cannot be disrupted by DNA damage, rendering p53 inactive. Methods: To determine whether the p53 response phenotype is influenced differentially in cells with variable mdm2 genotypes, we compared responses to DNA damage and targeted p53-Mdm2 complex disruption by Nutlin-3 in the following wild-type p53 human cancer cell lines: A875 and CCF-STTC-1 (C/C for mdm2 SNP309), SJSA-1 {mdm2 genomic amplification and T/T for mdm2 SNP309), MCF-7 (estrogen-induced Mdm2 overexpres- sion and T/C for mdm2 SNP309), ML-1 and H460 (T/T for mdm2 SNP309), and K562 (p53- null and T/C for mdm2 SNP309). We also examined mdm2 gene-splicing patterns in these lines by cloning and sequencing analyses. Results: While Mdm2-overexpressing C/C cells were resistant to p53 activation by DNA damage, they were sensitive to Nutlin-3. Strikingly, the p53 C1 checkpoint in C/C cells was activated by Nutlin-3 but not by etoposide, whereas in other Mdm2-overexpressing cells, both drugs activated p53 and subsequent C1 arrest or apoptosis. cDNA clones lacking exons 5-9 were generated at a high frequency in cells overexpressing Mdm2. Conclusion: Nutlin-3 and DNA damage distinguish a differential phenotype in human cancer cells with C/C mdm2 SNP309 from other Mdm2 overexpressers. Categorization of the Mdm2 isoforms produced and their influence on p53 activity will help in characterization and treatment development for different cancers.

Original languageEnglish (US)
Pages (from-to)S2-1-S2-8
JournalEthnicity and Disease
Volume18
Issue number2 SUPPL. 2
StatePublished - Mar 2008

Keywords

  • Mdm2
  • Nutlin-3
  • P53
  • Phenotype
  • SNP309

ASJC Scopus subject areas

  • Epidemiology

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