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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

PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells

Muxiang Zhou1, Lubing Gu, Harry W Findley

  • 1Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Emory University School of Medicine, 2040 Ridgewood Drive N.E., Atlanta, GA 30322, USA. mzhou@emory.edu

Cancer Research
|October 16, 2003
PubMed

Insights

The tumor suppressor PTEN enhances sensitivity to doxorubicin in acute lymphoblastic leukemia (ALL) by inhibiting MDM2 and protecting p53. Loss of PTEN leads to chemoresistance via MDM2-mediated antiapoptotic mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • PTEN (phosphatase and tensin homolog) is a tumor suppressor involved in apoptosis regulation.
  • MDM2 (mouse double minute 2 homolog) plays a role in chemoresistance.
  • PI3K/Akt signaling pathway is implicated in cellular survival and proliferation.

Purpose of the Study:

  • To investigate the role of PTEN expression in MDM2-mediated chemoresistance in acute lymphoblastic leukemia (ALL).
  • To determine the relationship between PTEN, MDM2, and p53 in ALL cell lines treated with doxorubicin.

Main Methods:

  • Analysis of PTEN and MDM2 expression in 9 ALL cell lines.
  • Assessment of doxorubicin sensitivity in ALL cell lines.
  • Forced expression of PTEN in a PTEN-negative ALL cell line (EU-1).
  • Immunoprecipitation and cotransfection assays to study protein interactions.

Main Results:

  • High PTEN expression correlated with doxorubicin sensitivity, while PTEN loss resulted in resistance.
  • Forced PTEN expression in resistant cells decreased growth and increased doxorubicin sensitivity.
  • PTEN physically binds to p53, attenuating MDM2-mediated inhibition of p53.
  • PTEN influences MDM2 cellular localization, shifting it from the nucleus to the cytoplasm.

Conclusions:

  • PTEN inhibits MDM2 and protects p53 through both PI3K/Akt-dependent and -independent pathways.
  • Loss of PTEN function contributes to chemoresistance in ALL by activating MDM2-mediated antiapoptotic mechanisms.
  • PTEN is a critical regulator of chemoresistance in ALL, making it a potential therapeutic target.

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