Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53

Lindsey Mayo, John Turchi, Steven J. Berberich

Research output: Contribution to journalArticle

201 Citations (Scopus)

Abstract

In response to genotoxic stress, the p53 tumor suppressor protein exerts a G1 cell cycle arrest that is dependent on its ability to transactivate downstream target genes. This p53-dependent G1 block is reversed by the binding of Mdm-2 to p53, preventing further transactivation. Interestingly, following DNA damage, the mdm-2 gene is also transcriptionally activated by p53, and therefore, the question of how p53 can continue to transactivate genes in the presence of its own negative regulator has remained unanswered. Here, we provide evidence that phosphorylation of Mdm-2 protein by DNA- dependent protein kinase (DNA-PK) blocks its ability to associate with p53 and regulate p53 transactivation. The data support a model by which DNA-PK activation by DNA damage and phosphorylation of Mdm-2 renders the Mdm-2 protein unable to inhibit p53 transactivation, resulting in cell cycle arrest. Following DNA repair, the loss of DNA-PK activity results in newly synthesized Mdm-2 protein that is unphosphorylated and, therefore, capable of binding to p53, allowing cell cycle progression.

Original languageEnglish (US)
Pages (from-to)5013-5016
Number of pages4
JournalCancer Research
Volume57
Issue number22
StatePublished - Nov 15 1997
Externally publishedYes

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Proto-Oncogene Proteins c-mdm2
DNA-Activated Protein Kinase
Transcriptional Activation
DNA Damage
Phosphorylation
Genes
G1 Phase Cell Cycle Checkpoints
Tumor Suppressor Protein p53
Cell Cycle Checkpoints
DNA Repair
Cell Cycle

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. / Mayo, Lindsey; Turchi, John; Berberich, Steven J.

In: Cancer Research, Vol. 57, No. 22, 15.11.1997, p. 5013-5016.

Research output: Contribution to journalArticle

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