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Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced

Michael I Carr1, Justine E Roderick2, Hugh S Gannon1

  • 1Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Cell Reports
|August 30, 2016
PubMed

Insights

Phosphorylating Mdm2 at S394 by ATM stabilizes p53, crucial for DNA damage response. This phosphorylation delays lymphoma in mice, but inhibiting it aids bone marrow recovery after radiation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • ATM-Mdm2 signaling is critical for p53 stabilization and activation following DNA damage.
  • Mdm2 phosphorylation at serine 394 (S394) by ATM is a key regulatory step.
  • The in vivo role of Mdm2-S394 phosphorylation in the DNA damage response and tumorigenesis remains to be fully elucidated.

Purpose of the Study:

  • To investigate the in vivo function of Mdm2-S394 phosphorylation in regulating p53 activity and DNA damage response.
  • To determine the impact of Mdm2-S394 phosphorylation on lymphomagenesis and tumorigenesis.
  • To explore the therapeutic potential of modulating ATM-Mdm2 signaling in cancer and radiation therapy.

Main Methods:

  • Utilized Mdm2(S394A) knockin mice to study the effects of preventing Mdm2-S394 phosphorylation.
  • Assessed p53 stabilization and activation in DNA-damaged cells and lymphatic tissues.
  • Evaluated lymphomagenesis in Eμ-myc transgenic mice crossed with Mdm2(S394A) mice.
  • Analyzed hematopoietic stem and progenitor cell function in irradiated Mdm2(S394A) mice.

Main Results:

  • Mdm2-S394 phosphorylation regulates p53 activity and DNA damage response in lymphatic tissues by modulating Mdm2 stability.
  • Preventing Mdm2-S394 phosphorylation delays lymphomagenesis in Eμ-myc transgenic mice and obviates the need for p53 mutation.
  • Irradiated Mdm2(S394A) mice exhibit increased hematopoietic stem and progenitor cell function and decreased lymphomagenesis.

Conclusions:

  • ATM-mediated Mdm2-S394 phosphorylation plays a dual role in tumor suppression and DNA damage response.
  • Destabilizing Mdm2 via ATM phosphorylation is a potential therapeutic strategy for oncogene-induced malignancies.
  • Inhibiting Mdm2-S394 phosphorylation could mitigate bone marrow failure and prevent secondary malignancies after radiation or chemotherapy.

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