The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia

Troglio, Flavia; Echart, Cinara; Gobbi, A.; Pawson, Tony; Pelicci, Pier Giuseppe; Simoni, Maria Grazia De; Pelicci, Giuliana

doi:10.1073/pnas.0403283101

Cited by 36 publications

(39 citation statements)

References 25 publications

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“…RNA Isolation, cDNA Synthesis, and Real-Time Polymerase Chain Reaction Twenty-four hours after TBI, mice were killed and ipsilateral cortices dissected for gene expression analysis as previously described (Storini et al, 2005;Troglio et al, 2004). Briefly, total RNA was obtained from tissue specimens using the Trizol reagent (Gibco BRL, Kidlington, MD, USA).…”

Section: Transferase-mediated Dutp Nick End Labeling Stainingmentioning

confidence: 99%

Long-lasting protection in brain trauma by endotoxin preconditioning

Longhi

Gesuete

Perego

et al. 2011

J Cereb Blood Flow Metab

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We investigated the occurrence of endotoxin (lipopolysaccharide, LPS) preconditioning in traumatic brain injury (TBI), evaluating the time window of LPS-induced protection, its persistence, and the associated molecular mechanisms. Mice received 0.1 mg/kg LPS or saline intraperitoneally and subsequently TBI (by controlled cortical impact brain injury) at various time intervals. Mice receiving LPS 3, 5, or 7 days before TBI showed attenuated motor deficits at 1 week after injury compared with mice receiving saline. Those receiving LPS 5 days before injury had also a reduced contusion volume (7.9±1.3 versus 12±2.3 mm 3 ) and decreased cell death. One month after injury, the protective effect of LPS on contusion volume (14.5 ± 1.2 versus 18.2 ± 1.2 mm 3 ) and neurologic function was still present. Traumatic brain injury increased glial fibrillary acidic protein, CD11b, CD68, tumor necrosis factor-a, interleukin (IL)-10, and IL-6 mRNA expression 24 hours after injury. Lipopolysaccharide administered 5 (but not 9) days before injury increased the expression of CD11b (233%) and of interferon b (500%) in uninjured mice, while it reduced the expression of CD68 (by 46%) and increased that of IL-6 (by 52%) in injured mice. Lipopolysaccharide preconditioning conferred a long-lasting neuroprotection after TBI, which was associated with a modulation of microglia/macrophages activity and cytokine production.

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Section: Transferase-mediated Dutp Nick End Labeling Stainingmentioning

confidence: 99%

Long-lasting protection in brain trauma by endotoxin preconditioning

Longhi

Gesuete

Perego

et al. 2011

J Cereb Blood Flow Metab

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“…SHC3 is another candidate gene within the linked region based on its biological functions in activating the PI3K-PKB and MAPK pathways, 14,37 in regulating NMDA receptor function, 21 and the neuronal adaptive response to environmental stress. 22 In this study, 11 SNPs within SHC3, as well as the haplotypes of various combinations of these SNPs, were analyzed for associations with three adjusted ND measures in 602 nuclear families of either AA or EA origin. In light of the ethnic-specific characteristics of the SNPs among different ethnic groups 29,38 as well as known ethnic differences in ND and nicotine metabolism, 39,40 we not only performed association analysis on the combined sample (to increase power) but also on ethnicity-specific samples separately.…”

Section: Discussionmentioning

confidence: 99%

“…Such a protective effect might be explained by the stressameliorating function of SHC3. 22 For example, Troglio et al 22 reported that ShcC-null mice had significantly higher mortality, more severe neurological deficits, and increased apoptosis and size of the infarct area, compared with wild-type mice. Several epidemiological studies have documented strong associations between depression and smoking; 50,51 however, the presence of a causal relation between depression and smoking is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…21 Furthermore, a recent study revealed a novel function of Shc3 in the regulation of the neuronal adaptive response to environmental stress, suggesting that Shc3 functions as a stress-response gene that increases phosphatidylinositol 3-kinase activation and Akt phosphorylation after hypoxic or oxidation insults. 22 As a consequence, SHC3 expression might protect neuronal cells from stress-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

Sun

Lou

et al. 2006

Mol Psychiatry

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Our previous linkage study demonstrated that the 9q22-q23 chromosome region showed a 'suggestive' linkage to nicotine dependence (ND) in the Framingham Heart Study population. In this study, we provide further evidence for the linkage of this region to ND in an independent sample. Within this region, the gene encoding Src homology 2 domain-containing transforming protein C3 (SHC3) represents a plausible candidate for association with ND, assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m Test for ND (FTND). We utilized 11 single-nucleotide polymorphisms within SHC3 to examine the association with ND in 602 nuclear families of either African-American (AA) or EuropeanAmerican (EA) origin. Individual SNP-based analysis indicated three SNPs for AAs and one for EAs were significantly associated with at least one ND measure. Haplotype analysis revealed that the haplotypes A-C-T-A-T-A of rs12519-rs3750399-rs4877042-rs2297313-rs1547696-rs1331188, with a frequency of 27.8 and 17.6%, and C-T-A-G-T of rs3750399-rs4877042-rs2297313-rs3818668-rs1547696, at a frequency of 44.7 and 30.6% in the AA and Combined samples, respectively, were significantly inversely associated with the ND measures. In the EA sample, another haplotype with a frequency of 10.6%, A-G-T-G of rs1331188-rs1556384-rs4534195-rs1411836, showed a significant inverse association with ND measures. These associations remained significant after Bonferroni correction. We further demonstrated the SHC3 contributed 40.1-59.2% (depending on the ND measures) of the linkage signals detected on chromosome 9. As further support, we found that nicotine administered through infusion increased the Shc3 mRNA level by 60% in the rat striatum, and decreased it by 22% in the nucleus accumbens (NA). At the protein level, Shc3 was decreased by 38.0% in the NA and showed no change in the striatum. Together, these findings strongly implicate SHC3 in the etiology of ND, which represents an important biological candidate for further investigation.

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“…C Capone et al IL-1b observed as early as 24 h after injury and later on at 48 h. Instead, analysis of the expression of genes related to apoptosis (Troglio et al, 2004) revealed that 48, but not 24 h from ischemia, ST1942 decreases the expression of the proapoptotic gene Bax and increases that of the antiapoptotic Bcl-2 thus inducing a shift from a pro-to an antiapoptotic status. Notably, the decrease in Bax and the increase in Bcl-2 expression are wide and do not simply restore the expression observed in sham operated experimental groups.…”

Section: -Aminotetraline In Ischemic Injurymentioning

confidence: 98%

2-Aminotetraline Derivative Protects from Ischemia/Reperfusion Brain Injury with a Broad Therapeutic Window

Capone

Fabrizi

Piovesan

et al. 2006

Neuropsychopharmacol

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The effect of ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in ischemia/reperfusion injury in CD1 and C57BL/6 mice. ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after ischemia. Forty-eight hours after ischemia, ST1942 (25 mg/kg) reduced the infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by ST1942. Also examined was the effect of ST1942 on general and focal neurological deficits for 4 days after ischemia. Mice receiving the drug twice daily showed constantly reduced deficits. We then investigated the cortical mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after ischemia ST1942 treatment significantly counteracted ischemia-induced activation of IL-1b, TNFa, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving ST1942. In neuron-microglia cocultures, ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this 5-HT receptor subtype may represent a novel target for neuroprotective drugs in ischemic injury.

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The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia

Cited by 36 publications

References 25 publications

Long-lasting protection in brain trauma by endotoxin preconditioning

Long-lasting protection in brain trauma by endotoxin preconditioning

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

2-Aminotetraline Derivative Protects from Ischemia/Reperfusion Brain Injury with a Broad Therapeutic Window

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