The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32

Vaudry, David; Gonzalez, Bruno J.; Basille, Magali; Pamantung, Tommy Ferdinandus; Fontaine, Marc; Fournier, Alain; Vaudry, Hubert

doi:10.1073/pnas.97.24.13390

Cited by 126 publications

(85 citation statements)

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“…PACAP and its receptors are actively expressed in the central nervous system during development, notably in the germinative neuroepithelia and migratory zones (9, 10), suggesting that PACAP could be involved in the regulation of neurogenesis and͞or cell differentiation (11). In agreement with this hypothesis, in vitro studies have shown that PACAP exerts growth cone attraction in cultured neural tube precursors from Xenopus laevis (12) and promotes survival and differentiation of rat cerebellar granule cells (13)(14)(15). In vivo, PACAP injection at the surface of the cerebellum of 8-day-old rats increases the number of granule neurons in the internal granule cell layer (16).…”

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confidence: 68%

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Pituitary adenylate cyclase-activating polypeptide prevents the effects of ceramides on migration, neurite outgrowth, and cytoskeleton remodeling

Falluel‐Morel

Vaudry

Aubert

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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During neuronal migration, cells that do not reach their normal destination or fail to establish proper connections are eliminated through an apoptotic process. Recent studies have shown that the proinflammatory cytokine tumor necrosis factor ␣ (and its second messengers ceramides) and the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) play a pivotal role in the histogenesis of the cerebellar cortex. However, the effects of ceramides and PACAP on migration of cerebellar granule cells have never been investigated. Time-lapse videomicroscopy recording showed that C2-ceramide, a cell-permeable ceramide analog, and PACAP induced opposite effects on cell motility and neurite outgrowth. C2-ceramide markedly stimulated cell movements during the first hours of treatment and inhibited neuritogenesis, whereas PACAP reduced cell migration and promoted neurite outgrowth. These actions of C2-ceramide on cell motility and neurite outgrowth were accompanied by a disorganization of the actin filament network, depolarization of tubulin, and alteration of the microtubule-associated protein Tau. In contrast, PACAP strengthened the polarization of actin at the emergence cone, increased Tau phosphorylation, and abolished C2-ceramide-evoked alterations of the cytoskeletal architecture. The caspase-inhibitor Z-VAD-FMK, like PACAP, suppressed the ''dance of the death'' provoked by C2-ceramide. Finally, Z-VAD-FMK and the PP2A inhibitor okadaic acid both prevented the impairment of Tau phosphorylation induced by C2-ceramide. Taken together, these data indicate that the reverse actions of C2-ceramide and PACAP on cerebellar granule cell motility and neurite outgrowth are attributable to their opposite effects on actin distribution, tubulin polymerization, and Tau phosphorylation.neuronal migration ͉ sphingolipid D uring neurodevelopment, newly generated neurons migrate to reach their appropriate location in the brain and undergo neurite outgrowth to establish cell connections. Cell migration and synaptogenesis thus represent pivotal phases in maturation of the central nervous system. Neurons that have not established proper connection will be eliminated through apoptosis (1), and defects in the differentiation processes can lead to severe neuronal malformations. For instance, in the developing cerebellum, overexpression of the cytokine TNF␣ markedly alters granule cell migration and induces aberrant cerebellar cytoarchitecture (2). TNF stimulates the biosynthesis of ceramides, a class of second messengers that play a pivotal role during neurodevelopment (3, 4). In cerebellar granule neurons, ceramides trigger cell death through activation of the mitochondrial apoptotic pathway (5). Invalidation of acid sphingomyelinase, which catalyses the formation of ceramides, causes cerebellar axonal dystrophy and neurodegeneration (6), indicating that ceramides are involved in the control of neurogenesis and programmed cell death.Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-aa neuropeptide that belongs t...

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confidence: 68%

“…Recent studies have demonstrated that ceramides induce apoptosis of cerebellar granule cells (4,20), whereas PACAP promotes survival and neurite outgrowth in granule neurons (13,21). However, the effects of ceramides and PACAP on neuronal migration have never been investigated.…”

Section: Discussionmentioning

confidence: 99%

Pituitary adenylate cyclase-activating polypeptide prevents the effects of ceramides on migration, neurite outgrowth, and cytoskeleton remodeling

Falluel‐Morel

Vaudry

Aubert

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The neuroprotective effects of PACAP on granule neurons are primarily mediated through the cAMP͞protein kinase A signaling cascade (16,23,24,39). Because the inhibitory effect of PACAP on caspase-3 activity is mediated through the protein kinase A pathway (17), it is possible that inactivation of caspase-6 by PACAP can be ascribed to a protein kinase A-dependent phosphorylation (40). Alternatively, PACAP could activate endogenous blockers of caspase-6-like CIF (caspase-inhibitory factor) (40) or the p35 protein (41).…”

Section: Effects Of Pacap On Ethanol-induced Granule Cell Apoptosismentioning

confidence: 99%

“…In vivo studies have shown that injection of PACAP in the subarachnoid space increases the thickness of the internal granule cell layer and the number of granule neurons (14). Concurrently, in vitro experiments performed on cultured granule neurons have shown that PACAP acts as an antiapoptotic agent that inhibits caspase-3 activation (15)(16)(17). These observations prompted us to investigate the ability of PACAP to counteract the neurotoxic effects of ethanol on cerebellar granule neurons.…”

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Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Vaudry

Rousselle

Basille

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol exposure during development can cause brain malformations and neurobehavioral abnormalities. In view of the teratogenicity of ethanol, identification of molecules that could counteract the neurotoxic effects of alcohol deserves high priority. Here, we report that pituitary adenylate cyclase-activating polypeptide (PACAP) can prevent the deleterious effect of ethanol on neuronal precursors. Exposure of cultured cerebellar granule cells to ethanol inhibited neurite outgrowth and provoked apoptotic cell death. Incubation of granule cells with PACAP prevented ethanol-induced apoptosis, and this effect was not mimicked by vasoactive intestinal polypeptide, suggesting that PAC1 receptors are involved in the neurotrophic activity of PACAP. Ethanol exposure induced a strong increase of caspase-2, -3, -6, -8, and -9 activities, DNA fragmentation, and mitochondrial permeability. Cotreatment of granule cells with PACAP provoked a significant inhibition of all of the apoptotic markers investigated although the neurotrophic activity of PACAP could only be ascribed to inhibition of caspase-3 and -6 activities. These data demonstrate that PACAP is a potent protective agent against ethanol-induced neuronal cell death. The fact that PACAP prevented ethanol toxicity even when added 2 h after alcohol exposure, suggests that selective PACAP agonists could have potential therapeutic value for the treatment of fetal alcohol syndrome.cerebellum ͉ fetal alcohol syndrome ͉ development ͉ caspases

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“…The signal transduction pathways that mediate the anti-apoptotic effect of PACAP in cerebellar granule neurons have been investigated in several experimental models. Although the cAMP-PKA pathway has been implicated in the survival response (52-54), the role of phospholipase C and protein kinase C is still controversial (55,56). The MEK-ERK pathway is a major signaling pathway in neural cells that can be regulated by PKA, and recent studies have shown that inhibition of activation of the PKA-dependent MEK-ERK pathway abolishes the protective effect of PACAP on rat CGC (57).…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP-mediated Regulation of Transcription Factor Lot1 Expression in Cerebellar Granule Cells

Contestabile

Fila

Bartesaghi

et al. 2005

Journal of Biological Chemistry

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Lot1, a zinc finger transcription factor acting as a tumor suppressor gene on tumoral cells, is highly expressed during brain development. In developing rat cerebellum, Lot1 expression is high in cerebellar granule cells (CGC), a neuronal population undergoing postnatal neurogenesis. The time course of Lot1 cerebellar expression closely matches the expression of pituitary adenylate cyclaseactivating polypeptide (PACAP) receptors coupled to adenylyl cyclase. The aim of this study was to ascertain whether Lot1 expression is regulated by cAMP-dependent pathways and to identify mechanisms of Lot1 activation in CGC cultures. Our results show that Lot1 expression in CGC is cAMP-dependent, as treatments with either forskolin or PACAP-38 induced an increase in its expression at both the mRNA and protein levels. This effect on Lot1 expression was mimicked by dibutyryl cAMP and suppressed by protein kinase A and MEK inhibitors. In parallel, we found that treatments with forskolin and PACAP-38 in precursor CGC inhibited bromodeoxyuridine incorporation by 25 and 35%, respectively, indicating a negative effect on neuronal precursor proliferation. Luciferase reporter analysis and mutagenesis of the Lot1 promoter region indicated a crucial role of the AP1-binding site (located at ؊268 bp) in cAMP-induced Lot1 transcription. In addition, cotransfection experiments indicated that the c-Fos/c-Jun heterodimer is responsible for cAMP-dependent Lot1 transcriptional activation. In conclusion, our data demonstrate that, in CGC, Lot1 is under the transcriptional control of cAMP through an AP1 site regulated by the c-Fos/c-Jun heterodimer and suggest that this gene may be an important element of the cAMP-mediated pathway that regulates neuronal proliferation through the protein kinase A-MEK signaling cascade.Lot1 was initially characterized as a growth suppressor gene based on its decrease in a rat ovarian carcinoma cell line and hence called Lot1 for "lost in transformation" (1, 2). Its mouse ortholog, which is highly homologous to the human and rat genes (LOT1 and Lot1, respectively), was independently identified by Spengler et al. (3,4) and designated as Zac1. The anti-proliferative properties of Zac1 were demonstrated by its ability to induce apoptosis and concomitantly to arrest the cell cycle in G 1 in osteosarcoma cell lines (3). In accordance with its anti-proliferative role, ablation of Zac1 gene expression increases cell proliferation (3, 5). Lot1 encodes a transcription factor with seven zinc fingers of the Cys 2 -His 2 type. The presence of a specific DNA-binding region for Lot1 makes it a transcriptional regulator, acting either as an activator or a repressor of nuclear receptor activity (6 -8). A splice variant of Lot/ Zac1 was independently identified in humans by Kas et al. (7) and named PLAGL1 based on its homology to PLAG1 protein, encoded by the PLAG1 gene localized on chromosome 8q12 (9). Northern blot analysis of different tissues revealed the highest expression of Zac1 mRNA in the pituitary gland, lower levels of ...

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The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32

Cited by 126 publications

References 54 publications

Pituitary adenylate cyclase-activating polypeptide prevents the effects of ceramides on migration, neurite outgrowth, and cytoskeleton remodeling

Pituitary adenylate cyclase-activating polypeptide prevents the effects of ceramides on migration, neurite outgrowth, and cytoskeleton remodeling

Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Cyclic AMP-mediated Regulation of Transcription Factor Lot1 Expression in Cerebellar Granule Cells

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