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Updated: Mar 21, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

Anusha Sriraman1, Marija Radovanovic1, Magdalena Wienken1

  • 1Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany.

Oncotarget
|May 18, 2016
PubMed

Insights

Inhibiting Mdm2 and Wip1 simultaneously enhances p53 activity and tumor suppression in cancer cells. This combination therapy, using Mdm2 antagonists and Wip1 inhibitors, shows synergistic effects on cell proliferation and senescence.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeting Mdm2 oncoprotein can restore p53 function for tumor suppression.
  • Mdm2-antagonizing drugs like Nutlin-3a may not sustainably inhibit cancer cell growth.
  • Wip1 (PPM1D) is another negative regulator of p53 that can be targeted.

Purpose of the Study:

  • To investigate the combined effect of inhibiting Mdm2 and Wip1 on p53 activity and cancer cell growth.
  • To determine if dual inhibition overcomes limitations of Mdm2 antagonists alone.

Main Methods:

  • Treatment of p53-proficient and p53-deficient cells with Nutlin-3a and Wip1 inhibitor GSK2830371.
  • Analysis of p53 phosphorylation and acetylation.
  • Deep sequencing analysis of RNA to assess gene expression changes.
  • Evaluation of cell proliferation, senescence, and cell cycle arrest (G2/M).

Main Results:

  • Combined Nutlin-3a and GSK2830371 synergistically inhibited proliferation in p53-proficient cells.
  • Dual inhibition enhanced p53 phosphorylation (Ser 15) and acetylation (Lys 382).
  • Combination therapy led to increased p53 target gene expression, senescence, and G2/M accumulation.

Conclusions:

  • Simultaneous inhibition of Mdm2 and Wip1 potentiates p53-mediated tumor suppression.
  • Wip1 inhibition may enhance the efficacy of Mdm2 antagonists in cancer treatment.
  • Dual targeting offers a promising strategy for overcoming resistance to Mdm2-targeting drugs.
Keywords:
Mdm2Wip1/PPM1Dkinasep53phosphatase

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