Controlling the Mdm2-Mdmx-p53 circuit

David L. Waning, Jason A. Lehman, Christopher N. Batuello, Lindsey Mayo

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The p53 tumor suppressor is a key protein in maintaining the integrity of the genome by inducing either cell cycle arrest or apoptosis following cellular stress signals. Two human family members, Mdm2 and Mdmx, are primarily responsible for inactivating p53 transcription and targeting p53 protein for ubiquitin-mediated degradation. In response to genotoxic stress, post-translational modifications to p53, Mdm2 and Mdmx stabilize and activate p53. The role that phosphorylation of these molecules plays in the cellular response to genotoxic agents has been extensively studied with respect to cancer biology. In this review, we discuss the main phosphorylation events of p53, Mdm2 and Mdmx in response to DNA damage that are important for p53 stability and activity. In tumors that harbor wild-type p53, reactivation of p53 by modulating both Mdm2 and Mdmx signaling is well suited as a therapeutic strategy. However, the rationale for development of kinase inhibitors that target the Mdm2-Mdmx-p53 axis must be carefully considered since modulation of certain kinase signaling pathways has the potential to destabilize and inactivate p53.

Original languageEnglish
Pages (from-to)1576-1593
Number of pages18
JournalPharmaceuticals
Volume3
Issue number5
DOIs
StatePublished - 2010

Fingerprint

DNA Damage
Phosphotransferases
Phosphorylation
Neoplasms
Protein Transport
Post Translational Protein Processing
Ubiquitin
Cell Cycle Checkpoints
Genome
Apoptosis
Proteins
Therapeutics

Keywords

  • Kinase inhibitor
  • Mdm2
  • Mdmx
  • P53
  • Phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

Cite this

Waning, D. L., Lehman, J. A., Batuello, C. N., & Mayo, L. (2010). Controlling the Mdm2-Mdmx-p53 circuit. Pharmaceuticals, 3(5), 1576-1593. https://doi.org/10.3390/ph3051576

Controlling the Mdm2-Mdmx-p53 circuit. / Waning, David L.; Lehman, Jason A.; Batuello, Christopher N.; Mayo, Lindsey.

In: Pharmaceuticals, Vol. 3, No. 5, 2010, p. 1576-1593.

Research output: Contribution to journalArticle

Waning, DL, Lehman, JA, Batuello, CN & Mayo, L 2010, 'Controlling the Mdm2-Mdmx-p53 circuit', Pharmaceuticals, vol. 3, no. 5, pp. 1576-1593. https://doi.org/10.3390/ph3051576
Waning, David L. ; Lehman, Jason A. ; Batuello, Christopher N. ; Mayo, Lindsey. / Controlling the Mdm2-Mdmx-p53 circuit. In: Pharmaceuticals. 2010 ; Vol. 3, No. 5. pp. 1576-1593.
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