Protein tyrosine phosphatases are up-regulated and participate in cell death induced by polyglutamine expansion

J Biol Chem. 2002 Nov 15;277(46):44208-13. doi: 10.1074/jbc.M206890200. Epub 2002 Sep 10.

Abstract

Polyglutamine expansion is the cause of several neurodegenerative diseases. An in vitro model of polyglutamine-induced neuronal cell death was developed using truncated mutant huntingtin (Htt) and PC12 cells. Cell death was specifically observed in cells expressing a truncated mutant huntingtin-green fluorescence protein (GFP) fusion protein with 118 glutamine repeats (Gln(118)), as demonstrated by the release of lactate dehydrogenase (LDH). To gain further insights into the mechanisms of polyglutamine expansion-induced cell death, the Affymetrix rat genome array U34A was used to investigate gene expression changes associated with polyglutamine-mediated protein aggregation and cell death. Among the up-regulated genes, the increase of four protein tyrosine phosphatases (PTPs) was further confirmed by real-time quantitative reverse transcription PCR. Protein expression of mitogen activated protein (MAP) kinase phosphatase 1 (MKP1) was also increased as demonstrated by Western blot. Furthermore, phosphorylation of MAP kinase extracellular signal-regulated kinase 1/2 (ERK1/2) was substantially reduced in association with protein aggregation, and two general PTP inhibitors, sodium orthovanadate and bpV(pic), dramatically rescued the cells from polyglutamine-induced cell death. These results suggest that one or more of the PTPs are involved in the polyglutamine-induced cell death.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Death
  • Cell Survival
  • Green Fluorescent Proteins
  • Huntingtin Protein
  • Luminescent Proteins / metabolism
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • PC12 Cells
  • Peptides / metabolism*
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / metabolism*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transfection
  • Up-Regulation*
  • Vanadates / pharmacology

Substances

  • Htt protein, rat
  • Huntingtin Protein
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Green Fluorescent Proteins
  • polyglutamine
  • Vanadates
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases