Protein tyrosine phosphatases are up-regulated and participate in cell death induced by polyglutamine expansion.
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.
Wu
Zhi-Liang
ZL
Cephalon, West Chester, Pennsylvania 19380, USA. zwu@cephalon.com
O'Kane
Teresa M
TM
Scott
Richard W
RW
Savage
Mary J
MJ
Bozyczko-Coyne
Donna
D
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002470:Cell Survival; D049452:Green Fluorescent Proteins; D000071058:Huntingtin Protein; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D014638:Vanadates / Q000494:pharmacology
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D014638:Vanadates; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases