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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

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Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex:

Casimiro Gerarduzzi1, Anna de Polo1, Xue-Song Liu1

  • 1From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115.

The Journal of Biological Chemistry
|October 26, 2016
PubMed

Insights

The human epidermal growth factor receptor 4 (Her4) stabilizes the MDMX-MDM2 complex, inhibiting the tumor suppressor p53. Targeting this Her4-MDMX-MDM2 interaction, specifically MDMX phosphorylation, can restore p53 activity in cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Deregulated receptor tyrosine kinase (RTK) signaling drives tumorigenesis and therapy resistance.
  • The tumor suppressor p53 plays a critical role in preventing cancer.
  • Mechanisms linking RTK signaling to p53 regulation are not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms by which the RTK human epidermal growth factor receptor 4 (Her4) impacts tumor suppressor p53.
  • To investigate the role of Her4 in regulating the stability of the MDMX-MDM2 complex.
  • To identify novel therapeutic strategies targeting RTK-mediated signals for p53 restoration.

Main Methods:

  • Activation of Her4 via overexpression or Neuregulin-1 ligand binding.
  • Assessment of p53 transcriptional activity using luciferase assays and mRNA analysis of p53 target genes.
  • Phospho-proteomics to identify Her4-induced posttranslational modifications on MDMX.
  • Inhibition of MDMX phosphorylation at Ser-314 using site-directed mutagenesis (Ser-to-Ala) and CDK4/6 kinase inhibitors.

Main Results:

  • Her4 activation stabilizes the MDMX-MDM2 complex, suppressing p53 transcriptional activity.
  • A novel Her4-induced posttranslational modification on MDMX at Ser-314 was identified as a putative CDK4/6 phosphorylation site.
  • Inhibition of MDMX Ser-314 phosphorylation blocked Her4-induced MDMX-MDM2 stabilization and restored p53 activity.

Conclusions:

  • Her4 inhibits p53 by stabilizing the MDMX-MDM2 complex through phosphorylation of MDMX at Ser-314.
  • Targeting the Her4-MDMX-MDM2 axis, particularly MDMX phosphorylation, represents a potential therapeutic strategy in cancer.
  • Understanding RTK-mediated p53 regulation provides insights into carcinogenesis and offers avenues for novel cancer therapies.
Keywords:
ErbB4MDMXbreast cancercyclin-dependent kinase (CDK)mouse double minute 2 homolog (MDM2)p53radiotherapyreceptor tyrosine kinase

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