Specific up‐regulation of GADD153/CHOP in 1‐methyl‐4‐phenyl‐pyridinium‐treated SH‐SY5Y cells

Conn, Kelly J.; Gao, Wenwu; Ullman, M. David; McKeon-O'Malley, Catherine; Eisenhauer, Patricia B.; Fine, Richard E.; Wells, John M.

doi:10.1002/jnr.10252

Cited by 30 publications

(28 citation statements)

References 44 publications

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“…3). In support of the present findings, microarray analysis of MPP ϩ -treated SH-SY5Y cells also resulted in an up-regulation of CHOP, albeit with a much later, more prolonged time course (46). Similarly, microarray analysis of the dopaminergic cell line, SN4741, revealed induction of stress indices following MPP ϩ treatment (47).…”

Section: -Ohda But Not Mpp ϩ Induces Components Of the Upr Pathwasupporting

confidence: 88%

Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons

Holtz

O’Malley

2003

Journal of Biological Chemistry

346

257

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Genes associated with Parkinson's disease (PD) have suggested a role for ubiquitin-proteasome dysfunction and aberrant protein degradation in this disorder. Inasmuch as oxidative stress has also been implicated in PD, the present study examined transcriptional changes mediated by the Parkinsonism-inducing neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP ؉ ) in a dopaminergic cell line. Microarray analysis of RNA isolated from toxin treated samples revealed that the stress-induced transcription factor CHOP/Gadd153 was dramatically up-regulated by both 6-OHDA and MPP ؉ . Treatment with 6-OHDA also induced a large number of genes involved in endoplasmic reticulum stress and unfolded protein response (UPR) such as ER chaperones and elements of the ubiquitinproteasome system. Reverse transcription-PCR, Western blotting, and immunocytochemical approaches were used to quantify and temporally order the UPR pathways involved in neurotoxin-induced cell death. 6-OHDA, but not MPP ؉ , significantly increased hallmarks of UPR such as BiP, c-Jun, and processed Xbp1 mRNA. Both toxins increased the phosphorylation of UPR proteins, PERK and eIF2␣, but only 6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is capable of triggering multiple pathways associated with UPR, whereas MPP ؉ exhibits a more restricted response. The involvement of UPR in these widely used neurotoxin models supports the role of ubiquitin-proteasome pathway dysfunction in PD.

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Section: -Ohda But Not Mpp ϩ Induces Components Of the Upr Pathwasupporting

confidence: 88%

Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons

Holtz

O’Malley

2003

Journal of Biological Chemistry

346

257

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“…In this respect, the cell death caused by DA resembles the process described in vitro for MPP + [30], 6-OHDA [31] and DA itself [32], and in vivo for striatally administered 6-OHDA [33]. GADD153 increased in rat nigra after 6-OHDA treatment, in accordance with results described in cell cultures [16,34], but not after DA administration. The difference in this effect suggests that GADD153 increases in response to increased production of oxygen radicals by 6-OHDA.…”

Section: Discussionsupporting

confidence: 86%

Intranigral Dopamine Toxicity and α-Synuclein Response in Rats

Gómez-Santos¹,

Giménez-Xavier

Ferrer

et al. 2006

Neurochem Res

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There is increasing evidence that, in addition to its function as the main neurotransmitter in the nigrostriatal pathway, dopamine (DA) may be neurotoxic in certain conditions. In this study, the toxicity of DA was assessed by direct injection into the substantia nigra of anaesthetised rats, and its effects were compared with those of 6-hydroxydopamine. Brains were removed 1, 2 and 3 weeks after the lesion for histological or neurochemical analysis. DA caused a significant loss of 35% of tyrosine hydroxylase-positive neurons in the pars compacta of substantia nigra and a 40% reduction of striatal DA content. Cells with signs compatible with both apoptosis and autophagy were observed. GADD153, a parameter of endoplasmic reticulum stress, was strongly induced by 6-hydroxydopamine but not by DA. DA increased the alpha-synuclein content 1 week after the lesion (but not at the later times analyzed) in tyrosine hydroxylase-positive and in non-dopaminergic fibers of pars reticulata. The alpha-synuclein increase may be a physiological temporal response to DA accumulation and/or to cell damage, but the simultaneous presence of alpha-synuclein and DA in the cell cytoplasm at concentration higher than normal is not exempt from risk. In fact, their incubation in a free cell system gives a stable dimerized form of alpha-synuclein that has been described as the critical rate-limiting step for its abnormal fibrillation.

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“…The C/EBP homologous protein CHOP, a growth arrest gene, is expressed in several tumour tissues and cell lines, like hepatoma, neuroblastoma, myeloid and colon cancer cells (Friedman, 1996;Conn et al, 2002;Kim et al, 2002;Scott and Loo, 2004). Expression levels of CHOP and C/EBPb correlate with the invasiveness of human colorectal cancer (Rask et al, 2000), and the cancer chemopreventive substance curcumin enhances CHOP expression in colonocytes (HCT-116) containing a mutant b-Catenin (Scott and Loo, 2004).…”

Section: Introductionmentioning

confidence: 99%

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, b-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.

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Specific up‐regulation of GADD153/CHOP in 1‐methyl‐4‐phenyl‐pyridinium‐treated SH‐SY5Y cells

Cited by 30 publications

References 44 publications

Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons

Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons

Intranigral Dopamine Toxicity and α-Synuclein Response in Rats

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

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