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 (Gln118), 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.

[1]  L. Ellerby,et al.  Calpain Activation in Huntington's Disease , 2002, The Journal of Neuroscience.

[2]  Cheng Song,et al.  Expression of Full-length Polyglutamine-expanded Huntingtin Disrupts Growth Factor Receptor Signaling in Rat Pheochromocytoma (PC12) Cells* , 2002, The Journal of Biological Chemistry.

[3]  M. Gorospe,et al.  Transcriptional Induction of MKP-1 in Response to Stress Is Associated with Histone H3 Phosphorylation-Acetylation , 2001, Molecular and Cellular Biology.

[4]  K. Seta,et al.  Hypoxia-induced Regulation of MAPK Phosphatase-1 as Identified by Subtractive Suppression Hybridization and cDNA Microarray Analysis* , 2001, The Journal of Biological Chemistry.

[5]  D. Rubinsztein,et al.  Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease. , 2001, Human molecular genetics.

[6]  D. Bozyczko‐Coyne,et al.  CEP‐1347/KT‐7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Aβ‐induced cortical neuron apoptosis , 2001, Journal of neurochemistry.

[7]  S. Oliverio,et al.  Early Alterations in Gene Expression and Cell Morphology in a Mouse Model of Huntington's Disease , 2000, Journal of neurochemistry.

[8]  S. W. Davies,et al.  Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C A Ross,et al.  Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. , 2000, Human molecular genetics.

[10]  S. Keyse,et al.  Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. , 2000, Current opinion in cell biology.

[11]  C. Ross,et al.  Nuclear Targeting of Mutant Huntingtin Increases Toxicity , 1999, Molecular and Cellular Neuroscience.

[12]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[13]  K. Moulder,et al.  Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length , 1999, The Journal of Neuroscience.

[14]  Steven Finkbeiner,et al.  Huntingtin Acts in the Nucleus to Induce Apoptosis but Death Does Not Correlate with the Formation of Intranuclear Inclusions , 1998, Cell.

[15]  J. Mandel,et al.  A cellular model that recapitulates major pathogenic steps of Huntington's disease. , 1998, Human molecular genetics.

[16]  R. Graham,et al.  A Novel Putative Protein-tyrosine Phosphatase Contains a BRO1-like Domain and Suppresses Ha-ras-mediated Transformation* , 1998, The Journal of Biological Chemistry.

[17]  Michael R. Hayden,et al.  The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity , 1998, The Journal of cell biology.

[18]  C A Ross,et al.  Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. , 1998, Human molecular genetics.

[19]  Dale E. Bredesen,et al.  Caspase Cleavage of Gene Products Associated with Triplet Expansion Disorders Generates Truncated Fragments Containing the Polyglutamine Tract* , 1998, The Journal of Biological Chemistry.

[20]  A. Hackam,et al.  Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates , 1998, Nature Genetics.

[21]  Mark Turmaine,et al.  Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation , 1997, Cell.

[22]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[23]  M. Hayden,et al.  Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract , 1996, Nature Genetics.

[24]  D. Alessi,et al.  Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual‐specificity phosphatase. , 1996, The EMBO journal.

[25]  S. Aaronson,et al.  A novel dual specificity phosphatase induced by serum stimulation and heat shock. , 1994, The Journal of biological chemistry.

[26]  K. Guan,et al.  Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase. , 1993, The Journal of biological chemistry.

[27]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[28]  S. Keyse,et al.  Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase , 1992, Nature.

[29]  H. Zoghbi,et al.  Glutamine repeats and neurodegeneration. , 2000, Annual review of neuroscience.