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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

Published on: August 4, 2019

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NEK10 tyrosine phosphorylates p53 and controls its transcriptional activity

Nasir Haider1,2, Previn Dutt2, Bert van de Kooij3

  • 1Department of Medical Biophysics, Princess Margaret Cancer Research Tower, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Oncogene
|June 21, 2020
PubMed

Insights

NimA-related kinase 10 (NEK10) regulates the tumor suppressor p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Genotoxic stress activates kinase signaling cascades, including those targeting the tumor suppressor p53, crucial for the DNA damage response (DDR).
  • Defects in DDR pathways contribute to mutation accumulation and tumorigenesis.
  • Members of the NimA-related kinase (NEK) family, such as NEK1, NEK10, and NEK11, are implicated in DDR pathways.

Purpose of the Study:

  • To investigate the role of NEK10 in the DNA damage response (DDR).
  • To elucidate the mechanism by which NEK10 regulates p53 transcriptional activity.
  • To determine the clinical relevance of NEK10 in breast cancer prognosis.

Main Methods:

  • Investigated NEK10's function in regulating p53 transcriptional activity via tyrosine phosphorylation.
  • Analyzed the effect of NEK10 loss on cellular proliferation and p53-dependent transcription.
  • Utilized p53 mutants (Y327F) to assess the impact of phosphorylation at Y327.
  • Assessed sensitivity of NEK10-deficient cells to DNA-damaging agents.
  • Correlated NEK10 and TP53-target gene expression with breast cancer outcomes.

Main Results:

  • NEK10 directly phosphorylates p53 on tyrosine 327 (Y327), demonstrating specific substrate recognition.
  • Loss of NEK10 leads to increased cellular proliferation by altering p53-dependent transcriptional output.
  • A p53 Y327F mutant exhibits hypomorphic activity, resulting in an attenuated p53-mediated transcriptional response.
  • NEK10-deficient cells show increased sensitivity to DNA-damaging agents.
  • A combined score of NEK10 and TP53-target gene expression independently predicts favorable outcomes in breast cancer.

Conclusions:

  • NEK10 plays a critical role in regulating p53 transcriptional activity through direct phosphorylation at Y327.
  • NEK10-mediated regulation of p53 impacts cellular proliferation and DNA damage sensitivity.
  • NEK10 and its downstream targets represent potential biomarkers for predicting breast cancer prognosis.

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