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A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer

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Abstract

The p53 tumor suppressor requires tetramerization to function as an initiator of cell cycle arrest and/or apoptosis. Children in southern Brazil that exhibit an elevated incidence of adrenocortical carcinoma (ACC) harbor an Arg 337 to His mutation within the tetramerization domain of p53 (p53-R337H; 35 of 36 patients). The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild type domain (p53tet-wt). Furthermore, the stability of p53tet-R337H is highly sensitive to pH in the physiological range; this sensitivity correlates with the protonation state of the mutated His 337. These results demonstrate a pH-sensitive molecular defect of p53 (R337H), suggesting that pH-dependent p53 dysfunction is the molecular basis for these cases of ACC in Brazilian children.

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Figure 1: The p53 tetramerization domain.
Figure 2: p53tet-wt and p53tet-R337H adopt similar protein folds.
Figure 3: p53tet-R337H is destabilized in a pH-dependent manner.
Figure 4: Deprotonation of His 337 destabilizes p53tet-R337H.

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Acknowledgements

The authors would like to thank C. Arrowsmith for providing a plasmid containing the wild type p53tet DNA sequence, and members of the Molecular Oncogenesis Program at St. Jude and the Kriwacki and Zambetti laboratories for stimulating discussion. This work was supported by the American Lebanese Syrian Associated Charities, the American Cancer Society, the NCI and a Cancer Center (CORE) Support Grant.

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Authors and Affiliations

  1. Department of Structural Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, 38105, Tennessee, USA

    Enrico L. DiGiammarino, Amanda S. Lee, Weixing Zhang, Brian Bothner & Richard W. Kriwacki

  2. Department of Biochemistry, St. Jude Children's Research Hospital, 332 N.Lauderdale St., Memphis, 38105, Tennessee, USA

    Craig Cadwell & Gerard Zambetti

  3. Department of Molecular Sciences, University of Tennessee Health Sciences Center, Memphis, 38163, Tennessee, USA

    Brian Bothner, Gerard Zambetti & Richard W. Kriwacki

  4. Department of Hematology/Oncology, St. Jude Children's Research Hospital, 332 N.Lauderdale St., Memphis, 38105, Tennessee, USA

    Raul C. Ribeiro

  5. International Outreach Program, St. Jude Children's Research Hospital, 332 N.Lauderdale St., Memphis, 38105, Tennessee, USA

    Raul C. Ribeiro

Authors
  1. Enrico L. DiGiammarino
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  2. Amanda S. Lee
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  3. Craig Cadwell
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  4. Weixing Zhang
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  5. Brian Bothner
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  6. Raul C. Ribeiro
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  7. Gerard Zambetti
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  8. Richard W. Kriwacki
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Correspondence to Richard W. Kriwacki.

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DiGiammarino, E., Lee, A., Cadwell, C. et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Mol Biol 9, 12–16 (2002). https://doi.org/10.1038/nsb730

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