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Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin

Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin

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Authors

  • Ka-Kei Ho
  • Victoria A. McGuire
  • Chuay-Yeng Koo
  • Kyle W. Muir
  • Natalia de Olano
  • Evie Maifoshie
  • Douglas J. Kelly
  • Ursula B. McGovern
  • Lara J. Monteiro
  • Ana R. Gomes
  • Angel R. Nebreda
  • David G. Campbell
  • J. Simon C. Arthur
  • Eric W. -F. Lam

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Info

Original languageEnglish
Pages1545-1555
Number of pages11
JournalJournal of Biological Chemistry
Journal publication date6 Jan 2012
Journal number2
Volume287
DOIs
StatePublished

Abstract

FOXO3a is a forkhead transcription factor that regulates a multitude of important cellular processes, including proliferation, apoptosis, differentiation, and metabolism. Doxorubicin treatment of MCF-7 breast carcinoma cells results in FOXO3a nuclear relocation and the induction of the stress-activated kinase p38 MAPK. Here, we studied the potential regulation of FOXO3a by p38 in response to doxorubicin. Co-immunoprecipitation studies in MCF-7 cells demonstrated a direct interaction between p38 and FOXO3a. We also showed that p38 can bind and phosphorylate a recombinant FOXO3a directly in vitro. HPLC-coupled phosphopeptide mapping and mass spectrometric analyses identified serine 7 as a major site for p38 phosphorylation. Using a phosphorylated Ser-7 FOXO3a antibody, we demonstrated that FOXO3a is phosphorylated on Ser-7 in response to doxorubicin. Immunofluorescence staining studies showed that upon doxorubicin treatment, the wild-type FOXO3a relocalized to the nucleus, whereas the phosphorylation-defective FOXO3a (Ala-7) mutant remained largely in the cytoplasm. Treatment with SB202190 also inhibits the doxorubicin-induced FOXO3a Ser-7 phosphorylation and nuclear accumulation in MCF-7 cells. In addition, doxorubicin caused the nuclear translocation of FOXO3a in wild-type but not p38-depleted mouse fibroblasts. Together, our results suggest that p38 phosphorylation of FOXO3a on Ser-7 is essential for its nuclear relocalization in response to doxorubicin.

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