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Long lasting inhibition of Mdm2-p53 interaction potentiates mesenchymal stem cell differentiation into osteoblasts

Simona Daniele1, Chiara Giacomelli1, Deborah Pietrobono1

  • 1Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.

Biochimica Et Biophysica Acta. Molecular Cell Research
|February 1, 2019
PubMed

Insights

Long-lasting Mdm2-p53 dissociation promotes mesenchymal stem cell (MSC) differentiation into osteoblasts by modulating G protein-coupled receptors and downstream signaling pathways. This highlights the importance of Mdm2

Area of Science:

  • Cell Biology
  • Stem Cell Biology
  • Molecular Biology

Background:

  • Mesenchymal stem cell (MSC) differentiation into osteoblasts is regulated by complex transcriptional networks and signaling pathways.
  • The p53 and Murine double minute 2 (Mdm2) axis is a key regulator, with Mdm2 acting as a negative regulator of p53.
  • The precise signaling mechanisms governing the Mdm2-p53 axis in osteoblasts, including Mdm2's p53-independent functions, require further elucidation.

Purpose of the Study:

  • To investigate the effects of modulating the Mdm2-p53 interaction on MSC differentiation into osteoblasts.
  • To explore the downstream signaling pathways influenced by Mdm2 modulation during osteogenesis.

Main Methods:

  • Utilized short- and long-lasting inhibitors targeting the Mdm2-p53 complex to modulate Mdm2 activity.
  • Assessed MSC differentiation into osteoblasts.
  • Investigated the interaction between Mdm2 and G protein-coupled receptors kinase (GRK) 2.
  • Analyzed the functionality of A2B Adenosine Receptors (A2BARs) and downstream signaling molecules like cAMP, extracellular signal-regulated kinases (ERKs), and cAMP response element-binding protein (CREB).

Main Results:

  • Long-lasting dissociation of the Mdm2-p53 complex significantly enhanced MSC differentiation into osteoblasts.
  • Increased Mdm2 levels promoted its association with GRK2, a kinase involved in G protein-coupled receptor (GPCR) desensitization.
  • Long-lasting Mdm2-p53 dissociation led to decreased GRK2 levels, favoring A2BAR functionality and downstream pro-osteogenic signaling (cAMP, ERK, CREB activation).
  • Reversible Mdm2-p53 inhibition did not yield similar pro-osteogenic effects, suggesting the duration of Mdm2-p53 dissociation is critical.

Conclusions:

  • Long-lasting Mdm2-p53 dissociation is a key factor in promoting osteoblast differentiation from MSCs.
  • The Mdm2-p53 axis influences MSC fate through modulation of GPCR signaling, specifically A2BARs, and downstream effectors.
  • The temporal aspect of Mdm2-p53 interaction is crucial for regulating intracellular proteins involved in cell differentiation outcomes.
Keywords:
G protein-coupled receptors kinaseLong-lasting inhibitorsMesenchymal stem cellsMurine double minute 2Murine double minute 2-p53 complexOsteoblasts

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