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Mad1 destabilizes p53 by preventing PML from sequestering MDM2

Jun Wan1, Samuel Block2, Christina M Scribano1

  • 1Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, 53705, USA.

Nature Communications
|April 6, 2019
PubMed

Insights

Upregulated Mitotic Arrest Deficient 1 (Mad1) promotes breast cancer by preventing tumor suppressor p53 stabilization. Mad1 interacts with PML bodies, displacing MDM2 and leading to p53 degradation.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Oncology

Background:

  • Mitotic Arrest Deficient 1 (Mad1) is known for its role in the mitotic checkpoint.
  • Interphase functions of Mad1, independent of the mitotic checkpoint, are largely unknown.
  • Mad1 upregulation is frequently observed in human breast cancers.

Purpose of the Study:

  • To investigate the uncharacterized interphase roles of Mad1 in cancer.
  • To determine how Mad1 upregulation affects tumor suppressor p53 stability.
  • To elucidate the molecular mechanisms underlying Mad1's function in breast cancer.

Main Methods:

  • Investigated Mad1 localization in breast cancer and cultured cells using immunofluorescence.
  • Performed co-immunoprecipitation assays to study Mad1-PML and PML-MDM2 interactions.
  • Utilized cell-based assays to assess p53 stabilization and ubiquitination.
  • Generated orthotopic mammary tumor models to evaluate tumor growth in vivo.

Main Results:

  • Upregulated Mad1 prevents stress-induced stabilization of the tumor suppressor p53.
  • Mad1 localizes to ProMyelocytic Leukemia (PML) nuclear bodies and interacts with PML, an interaction enhanced by sumoylation.
  • Mad1 displaces MDM2 from PML, leading to increased p53 ubiquitination and degradation.
  • Mad1 upregulation accelerates mammary tumor growth and reduces p53 and p21 levels.

Conclusions:

  • Mad1 has an unexpected interphase role in promoting tumors.
  • Mad1 destabilizes p53 by interfering with the PML-MDM2 complex.
  • Mad1 upregulation contributes to breast cancer progression through p53 pathway inhibition.

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