Dopamine Induces Phenotypic Differentiation or Apoptosis in a Dose-Dependent Fashion: Involvement of the Dopamine Transporter and p53

Porat, Shai; Arumugam, Premkumar; Simantov, Rabi

doi:10.1159/000048730

Cited by 12 publications

(6 citation statements)

References 45 publications

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“…After 24 h of incubation with dopamine, anti-p53 antibody IB showed dosedependent increase of p53 immunoreactivity (Fig. 6A), which is consistent with the previous report by Porat et al (2001) that neurotoxic dopamine causes p53 activation in cells. SH-SY5Y cells were then transiently transfected with Pnut or Sep1, followed by incubation of dopamine, and the induction of characteristic apoptotic profile was confirmed by DNA fragmentation (Fig.…”

Section: Pnut and Sep1 Bind Directly To Syntaxinsupporting

confidence: 92%

Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 ubiquitin–protein ligase

Bae¹,

Kang²,

Park³

2007

Insect Biochemistry and Molecular Biology

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Section: Pnut and Sep1 Bind Directly To Syntaxinsupporting

confidence: 92%

Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 ubiquitin–protein ligase

Bae¹,

Kang²,

Park³

2007

Insect Biochemistry and Molecular Biology

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“…In free mitochondria, DA inhibited complex I at concentrations that differ depending on the study (Ben‐Shachar et al, 1995; Morikawa et al, 1996; Berman and Hastings, 1999). Dependent on the cell type and the assay conditions used, DA seems to be related to apoptosis, necrosis (Maruyama et al, 2000), differentiation (Porat et al, 2001), proliferation (Luo et al, 1999), or autophagy (Larsen et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Dopamine induces autophagic cell death and α‐synuclein increase in human neuroblastoma SH‐SY5Y cells

Gómez-Santos¹,

Ferrer²,

Santidrián³

et al. 2003

J of Neuroscience Research

177

115

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Free cytoplasmic dopamine may be involved in the genesis of neuronal degeneration in Parkinson's disease and other such diseases. We used SH-SY5Y human neuroblastoma cells to study the effect of dopamine on cell death, activation of stress-induced pathways, and expression of alpha-synuclein, the characteristic protein accumulated in Lewy bodies. We show that 100 and 500 microM dopamine causes a 40% and 60% decrease of viability, respectively, and triggers autophagy after 24 hr of exposure, characterized by the presence of numerous cytoplasmic vacuoles with inclusions. Dopamine causes mitochondrial aggregation in adherent cells prior to the loss of functionality. Plasma membrane and nucleus also maintain their integrity. Cell viability is protected by the dopamine transporter blocker nomifensine and the antioxidants N-acetylcysteine and ascorbic acid. Dopamine activates the stress-response kinases, SAPK/JNK and p38, but not ERK/MAPK or MEK, and increases alpha-synuclein expression. Both cell viability and the increase in alpha-synuclein expression are prevented by antioxidants; by the specific inhibitors of p38 and SAPK/JNK, SB203580 and SP600125, respectively; and by the inhibitor of autophagy 3-methyladenine. This indicates that oxidative stress, stress-activated kinases, and factors involved in autophagy up-regulate alpha-synuclein content. The results show that nonapoptotic death pathways are triggered by dopamine, leading to autophagy. These findings should be taken into account in the search for strategies to protect dopaminergic neurons from degeneration.

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“…In an effort to verify further the molecular mechanisms underlying dopamine‐induced apoptosis and cell differentiation (Simantov et al . 1996; Porat and Simantov 1999; Porat et al . 2001), the differential display PCR (DD–PCR) approach was used to determine changes in gene expression upon dopamine treatment.…”

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confidence: 99%

Mitochondrial voltage‐dependent anion channel is involved in dopamine‐induced apoptosis

Arumugam

Simantov

2002

Journal of Neurochemistry

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Neuronal NMB cells were used to determine changes in gene expression upon treatment with dopamine. Twelve differentially expressed cDNAs were identified and cloned, one of them having 99.4% sequence homology with isoform 2 of a voltage-dependent anion channel (VDAC-2). The known role of VDAC, a mitochondrial outer-membrane protein, in transport of anions, pore formation, and release of cytochrome C prompted us to investigate the possible role of VDAC gene family in dopamine-induced apoptosis. Semi-quantitative PCR analysis indicated that expression of the three VDAC isoforms was reduced by dopamine. Immunoblotting with anti-VDAC antibodies detected two VDAC protein bands of 33 and 34 kDa. Dopamine decreased differentially the immunoreactivity of the 34 kDa protein. Whether the decrease in VDAC expression influence the mitochondrial membrane potential (DYm) was determined with the dye Rhodamine-123. Dopamine indeed decreased the mitochondrial DYm, but the maximum effect was observed within 3 h, prior to the decrease in VDAC mRNA or protein levels. Cyclosporin A, a blocker of the mitochondrial pore complex, prevented the decrease in DYm, but did not rescue the cells from dopamine toxicity. To elucidate possible involvement of protease caspases in dopamine-induced apoptosis, the effect of the caspase inhibitor z-Val-Ala-Asp(Ome)-FMK (zVAD) was determined. zVAD decreased dopamine toxicity, yet it did not rescue the mitochondrial DYm drop. Dopamine also decreased ATP levels. Finally, transfection of NMB cells with pcDNA-VDAC decreased the cytotoxic effect of dopamine. These findings are in agreement with the notion that the mitochondria, and VDAC, are important participants in dopamine-induced apoptosis. It is now well established that dopamine triggers programmed neuronal cell death (apoptosis) in cultured cells (Ziv et al. 1994;Simantov et al. 1996;Coronas et al. 1997;Junn and Mouradian 2001). Oxidation products and reactive oxygen species (Jenner et al. 1992;Korsmeyer 1995), lipid peroxidation (Groc et al. 2001), depletion in glutathione (Riederer et al. 1989;Sofic et al. 1992;Gabbay et al. 1996), and other neurochemical changes (Olanow 1993) may be responsible for dopamine toxicity. The neurotoxins 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) and rotenone, often used as experimental models for Parkinson's disease, interact with the mitochondria and inhibit complex I activity (Gerlach et al. 1991;Cleeter et al. 1992;Tipton and Singer 1993). As to dopamine, however, the question of direct or indirect interaction with the mitochondria, and the potential molecular targets, is still enigmatic.Programmed cell death may be triggered by activation of mitochondria-dependent or -independent pathways, as reviewed by others (Green and Reed 1998;Li and Yuan 1999;Orth and Schapira 2001). The signaling pathway leading to apoptosis via the mitochondria is triggered by the binding of proteins of the Bcl 2 family, such as Bcl 2 , Bax and Bad, to the mitochondrial outer membrane. This interaction forms large pores i...

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Dopamine Induces Phenotypic Differentiation or Apoptosis in a Dose-Dependent Fashion: Involvement of the Dopamine Transporter and p53

Cited by 12 publications

References 45 publications

Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 ubiquitin–protein ligase

Drosophila melanogaster Parkin ubiquitinates peanut and septin1 as an E3 ubiquitin–protein ligase

Dopamine induces autophagic cell death and α‐synuclein increase in human neuroblastoma SH‐SY5Y cells

Mitochondrial voltage‐dependent anion channel is involved in dopamine‐induced apoptosis

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