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p90RSK Regulates p53 Pathway by MDM2 Phosphorylation in Thyroid Tumors

Immacolata Maietta1,2, Francesca Del Peschio1,2, Preziosa Buonocore1,2

  • 1Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, 80131 Napoli, Italy.

Cancers
|January 8, 2023
PubMed

Insights

The protein kinase p90RSK stabilizes MDM2, leading to the degradation of the tumor suppressor p53. Inhibiting p90RSK restores p53 activity, halting cancer cell proliferation and promoting apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • The tumor suppressor p53 is regulated by MDM2 through a feedback loop.
  • MDM2 targets p53 for degradation via ubiquitination.

Purpose of the Study:

  • To investigate the role of p90RSK in regulating MDM2 stability and p53 activity.
  • To explore the therapeutic potential of p90RSK inhibition in cancer.

Main Methods:

  • Kinase assay, immunoblot, and co-immunoprecipitation assays were used to study protein interactions and phosphorylation.
  • Pharmacological inhibition of p90RSK using BI-D1870.
  • Cell proliferation (BrdU assay, growth curve) and apoptosis (TUNEL assay) assays were performed.
  • Immunohistochemistry was used to evaluate protein expression in thyroid tumors.

Main Results:

  • p90RSK directly binds and phosphorylates MDM2 at serine 166.
  • This phosphorylation enhances MDM2 stability, promoting p53 ubiquitination and degradation.
  • Inhibition of p90RSK by BI-D1870 restores p53 function, leading to increased p21 and Bax, decreased Bcl-2, and suppressed cell proliferation and induced apoptosis.
  • p90RSK-mediated MDM2 stabilization was confirmed in primary thyroid tumors.

Conclusions:

  • p90RSK is a key regulator of MDM2 stability and consequently p53 activity.
  • Targeting p90RSK represents a potential therapeutic strategy for cancers with active p90RSK signaling.
Keywords:
MDM2apoptosiscancercell proliferationp53p90RSKproteasome degradationtargeted therapytumorigenesis

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