A suppressive role of the prolyl isomerase Pin1 in cellular apoptosis mediated by the death-associated protein Daxx

J Biol Chem. 2007 Dec 14;282(50):36671-81. doi: 10.1074/jbc.M704145200. Epub 2007 Oct 15.

Abstract

The death-associated protein Daxx is a multifunctional factor that regulates a variety of cellular processes, including transcription and apoptosis. Several previous reports have indicated that Daxx is induced upon oxidative stress and is then subjected to phosphorylation-based functional modification. However, the precise molecular events underlying these phosphorylation events remain largely unknown. We report in our current study that the peptidyl-prolyl isomerase Pin1 is highly overexpressed in malignant human gliomas and inhibits Daxx-mediated cellular apoptosis. The targeted inhibition of Pin1 by small interfering RNA in A172 glioblastoma cells significantly enhances the apoptotic response induced by hydrogen peroxide or stimulatory Fas antibodies. This is in turn accompanied by the increased induction of Daxx and the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase pathway. Furthermore, Pin1 binds to the phosphorylated Ser178-Pro motif in the Daxx protein, and Pin1 overexpression results in the rapid degradation of Daxx via the ubiquitin-proteasome pathway. Moreover, a Daxx-S178A mutant, which cannot interact with Pin1, demonstrates higher proapoptotic activity and is refractory to Pin1-mediated antiapoptotic effects. We further found that the expression levels of Pin1 inversely correlate with the degree of Daxx nuclear accumulation in human glioblastoma tissues. These results together indicate that Pin1-mediated prolyl isomerization plays an important role in the negative regulation of Daxx and thereby inhibits the oxidative stress-induced cellular apoptotic response, particularly in malignant tumor cells where Pin1 is often overexpressed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Cell Death / drug effects
  • Cell Death / genetics
  • Co-Repressor Proteins
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Molecular Chaperones
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidants / pharmacology
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Peptidylprolyl Isomerase / antagonists & inhibitors
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational* / drug effects
  • Protein Processing, Post-Translational* / genetics
  • RNA, Small Interfering / genetics
  • Ubiquitin / genetics
  • Ubiquitin / metabolism
  • fas Receptor / antagonists & inhibitors
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • Co-Repressor Proteins
  • DAXX protein, human
  • Molecular Chaperones
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oxidants
  • RNA, Small Interfering
  • Ubiquitin
  • fas Receptor
  • Hydrogen Peroxide
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Proteasome Endopeptidase Complex
  • PIN1 protein, human
  • Peptidylprolyl Isomerase