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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or

Lindsey D Mayo1, Young Rok Seo, Mark W Jackson

  • 1Department of Radiation Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA. lindsey.mayo@cwru.edu

The Journal of Biological Chemistry
|April 22, 2005
PubMed

Insights

Phosphorylation of p53 protein at serine 46 dictates its DNA damage response. This modification directs p53 to induce PTEN (phosphatase and tensin homolog deleted on chromosome ten) over MDM2, enhancing apoptosis and sustaining p53 function.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 plays a critical role in the cellular response to DNA damage, regulating apoptosis through target gene induction.
  • The balance between p53-mediated induction of MDM2 (mouse double minute 2 homolog) and PTEN (phosphatase and tensin homolog deleted on chromosome ten) influences cell fate following DNA damage.

Purpose of the Study:

  • To investigate the role of p53 phosphorylation at serine 46 in regulating the choice of target genes (MDM2 vs. PTEN) following DNA damage.
  • To elucidate the mechanism by which p53 serine 46 phosphorylation influences the apoptotic response and the p53-MDM2 feedback loop.

Main Methods:

  • Utilized chemotherapy to induce DNA damage in cells, varying doses to differentiate responses.
  • Employed site-directed mutagenesis to create non-phosphorylatable (S46A) and phosphorylation-mimicking (S46D) p53 mutants.
  • Assessed p53 target gene promoter activity (MDM2 and PTEN), protein expression, p53 phosphorylation status, and cellular apoptosis.

Main Results:

  • High-dose chemotherapy induced p53 phosphorylation at serine 46, leading to selective targeting of the PTEN promoter over MDM2.
  • The S46A p53 mutant preferentially targeted MDM2, while the S46D mutant (phosphorylation mimic) targeted PTEN.
  • Phosphorylation of p53 at serine 46 suppressed MDM2 induction, prevented the MDM2 autoregulatory feedback loop, and promoted PTEN-mediated apoptosis.

Conclusions:

  • Phosphorylation of p53 at serine 46 is a critical switch that determines its transcriptional targeting, favoring PTEN induction over MDM2.
  • PTEN induction by phosphorylated p53 sustains p53 function by inhibiting MDM2 nuclear translocation and creates an apoptotic amplification cycle.
  • This mechanism highlights a novel pathway where p53 serine 46 phosphorylation coordinates with PTEN to enhance cellular apoptosis in response to significant DNA damage.

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