Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism

Santini, Emanuela; Feyder, Michael; Gangarossa, Giuseppe; Bateup, Helen S.; Greengard, Paul; Fisone, Gilberto

doi:10.1074/jbc.m112.388413

Cited by 75 publications

(77 citation statements)

References 35 publications

(58 reference statements)

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“…However, previous experiments identified a population of TH-positive neurons in the dopaminedepleted mouse striatum, which increased after L-DOPA treatment (Darmopil et al, 2008). These neurons corresponded to MSNs, in agreement with previous observations (Tashiro et al, 1989) and with a recent study showing increased TH mRNA in D1R-expressing MSNs (Heiman et al, 2014). The number of striatal TH-positive neurons correlates with the level of FosB and with the severity of LID in hemiparkinsonian mice (Francardo et al, 2011;Heiman et al, 2014).…”

Section: Discussionsupporting

confidence: 81%

“…None of these genes was significantly blocked by SL327 pretreatment in our experiments, suggesting an ERK-independent pathway. D1R/PKA-mediated activation of ERK signaling after dopamine depletion has been suggested to play a major role in AIM development (Gerfen et al, 2002;Picconi et al, 2003;Santini et al, 2007;Westin et al, 2007;Schuster et al, 2008;Darmopil et al, 2009;Lindgren et al, 2009;Santini et al, 2009a;Santini et al, 2009b;Lebel et al, 2010;Santini et al, 2010;Francardo et al, 2011). The role of DARPP-32 in ERK activation by L-DOPA is debated because ERK phosphorylation was decreased in DARPP-32 KO mice in one study (Santini et al, 2007), but not in another one (Gerfen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of D1R and NMDA glutamate receptors can activate signaling cascades involving cAMP-dependent protein kinase (PKA), dopamine-and cAMP-regulated phosphoprotein of 32 kDa , and ERK in D1R-expressing MSNs . In 6-OHDA-lesioned animals, administration of L-DOPA activates a D1R-dependent Ras-ERK signaling pathway (Gerfen et al, 2002;Westin et al, 2007) that is correlated with the intensity of LID (Schuster et al, 2008;Darmopil et al, 2009;Lindgren et al, 2009;Santini et al, 2009a;Santini et al, 2009b;Lebel et al, 2010;Santini et al, 2010;Francardo et al, 2011). LID is blocked or decreased by pharmacological or genetic inhibition of the ERK pathway (Santini et al, 2007;.…”

Section: Introductionmentioning

confidence: 99%

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Gene Expression Analyses Identify Narp Contribution in the Development of l-DOPA-Induced Dyskinesia

Charbonnier-Beaupel¹,

Malerbi²,

Alcacer³

et al. 2015

J. Neurosci.

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In Parkinson's disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0 -6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by L-DOPA. L-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene Expression Analyses Identify Narp Contribution in the Development of l-DOPA-Induced Dyskinesia

Charbonnier-Beaupel¹,

Malerbi²,

Alcacer³

et al. 2015

J. Neurosci.

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“…In animal models of PD, D1R-dependent ERK1/2 activation in the DA-denervated striatum is accompanied by phosphorylation of nuclear targets, such as mitogen-and stress-activated protein kinase 1 (MSK1) and histone H3 (Westin et al, 2007;Santini et al, 2009;Alcacer et al, 2012). To verify whether ERK1/2 phosphorylation led to activation of downstream nuclear targets also in our ex vivo setting, we measured the levels of MSK1 phosphorylated at Ser 360 , an ERK-specific phosphorylation site (McCoy et al, 2005).…”

Section: Skf38393 Activates Erk1/2 Only In Da-denervated Striatamentioning

confidence: 99%

“…In parkinsonian rodents treated chronically with L-DOPA, the occurrence of dyskinetic behaviors is strongly correlated with a large activation of ERK1/2 signaling in DA-denervated striatal neurons via the D1R (Westin et al, Darmopil et al, 2009;Santini et al, 2009). Treatments capable of blunting the striatal activation of ERK1/2 by L-DOPA consistently attenuate the severity of dyskinesia in mouse, rat, and monkey models of PD (Santini et al, 2007;Schuster et al, 2008;Rylander et al, 2009;. L-DOPA-induced overactivation of ERK1/2 signaling is therefore widely considered as a hallmark of the maladaptive molecular plasticity associated with LID (Darmopil et al, 2009;Alcacer et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5

et al. 2014

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In animal models of ParkinsonЈs disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP 3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA-and Ca 2ϩ -dependent signaling pathways that is critically modulated by striatal mGluR5.

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MYC‐binding lncRNA EPIC1 promotes AKT‐mTORC1 signaling and rapamycin resistance in breast and ovarian cancer

Wang

Zhang

Wang

et al. 2020

Molecular Carcinogenesis

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AKT‐mTORC1 (mammalian target of rapamycin complex 1) signaling pathway plays a critical role in tumorigenesis and can be targeted by rapamycin. However, the underlying mechanism of how long noncoding RNA (lncRNAs) regulate the AKT‐mTORC1 pathway remains unclear. EPIC1 (epigenetically‐induced lncRNA 1) is a Myc‐binding lncRNA, which has been previously demonstrated to be overexpressed in multiple cancer types. In a pathway analysis including 4962 cancer patients, we observed that lncRNA EPIC1 expression was positively correlated with the AKT‐mTORC1 signaling pathway in more than 10 cancer types, including breast and ovarian cancers. RNA‐seq analysis of breast and ovarian cancer cells demonstrated that EPIC1‐knockdown led to the downregulation of genes in the AKT‐mTORC1 signaling pathway. In MCF‐7, OVCAR4, and A2780cis cell lines, EPIC1 knockdown and overexpression, respectively, inhibited and activated phosphorylated AKT and the downstream phosphorylation levels of 4EBP1 and S6K. Further knockdown of Myc abolished the EPIC1′s regulation of AKT‐mTORC1 signaling; suggested that the regulation of phosphorylation level of AKT, 4EBP1, and S6K by EPIC1 depended on the expression of Myc. Moreover, EPIC1 overexpressed MCF‐7, A2780cis, and OVCAR4 cells treated with rapamycin showed a significant decreasing in rapamycin mediated inhibition of p‐S6K and p‐S6 comparing with the control group. In addition, Colony Formation assay and MTT assay indicated that EPIC1 overexpression led to rapamycin resistance in breast and ovarian cancer cell lines. Our results demonstrated the lncRNA EPIC1 expression activated the AKT‐mTORC1 signaling pathway through Myc and led to rapamycin resistance in breast and ovarian cancer.

show abstract

Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism

Cited by 75 publications

References 35 publications

Gene Expression Analyses Identify Narp Contribution in the Development of l-DOPA-Induced Dyskinesia

Gene Expression Analyses Identify Narp Contribution in the Development of l-DOPA-Induced Dyskinesia

Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5

MYC‐binding lncRNA EPIC1 promotes AKT‐mTORC1 signaling and rapamycin resistance in breast and ovarian cancer

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