Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers

Chen Katz, Ana Maria Low-Calle, Joshua H. Choe, Oleg Laptenko, David Tong, Jazmine Saskya N. Joseph-Chowdhury, Francesca Garofalo, Yan Zhu, Assaf Friedler, Carol Prives*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.

Original languageAmerican English
Pages (from-to)430-447
Number of pages18
JournalGenes and Development
Issue number5-6
StatePublished - 1 Mar 2018

Bibliographical note

Publisher Copyright:
© 2018 Katz et al.


  • 20S proteasome
  • MDM2
  • Mutant p53
  • Nuclear export
  • p53 dimer
  • p53 tetramer


Dive into the research topics of 'Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers'. Together they form a unique fingerprint.

Cite this