Basal-like breast cancer is an aggressive disease with limited therapeutic options because these tumors frequently express the ‘triple-negative’ phenotype. We have recently reported that inducible ...nitric oxide synthase (NOS2) is a strong predictor of survival in patients with estrogen receptor negative ER(–) breast cancer, and that NOS2 expression is correlated with a basal-like phenotype. Recent reports also describe the pro-tumor effects of NO in breast and many other types of cancer. NO promotes cancer progression by activating several oncogenic signaling pathways such as extracellular signal-regulated kinases (ERK)-1/2, phosphoinositide 3-kinases (PI3K)/Akt, and c-Myc. Protein phosphatase 2A (PP2A) is a tumor suppressor that negatively regulates the same cancer-related signaling pathways that are activated by NO. PP2A activity is suppressed in tumor cells, but potential pharmacological agents have recently been described to increase PP2A activity in ER(–) breast cancer cells. We examine here the various functions of NO and PP2A in breast cancer and propose a novel mechanism by which activation of PP2A antagonizes NO signaling that promotes ER(–) breast cancer.
Conflicting evidence supports a role for tau as an essential neuronal cytoskeletal protein or as a redundant protein whose function can be fulfilled by other microtubule-associated proteins. To ...investigate the function of tau in axonogenesis, we created tau deficient mice by disrupting the TAU gene. The engineered mice do not express the tau protein, appear physically normal and are able to reproduce. In contrast to a previously reported tau knockout mouse, embryonic hippocampal cultures from tau deficient mice show a significant delay in maturation as measured by axonal and neuritic extensions. The classic technique of selectively enhancing axonal growth by growth on laminin substrates failed to restore normal neuronal maturation of tau knockout neurons. By mating human TAU-gene transgenic and tau knockout mice, we reconstituted tau-deficient neurons with human tau proteins and restored a normal pattern of axonal growth and neuronal maturation. The ability of human tau proteins to rescue tau-deficient mouse neurons confirms that tau expression affects the rate of neurite extension.
The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of the 40-residue Aβ(1−40) and 42-residue Aβ(1−42) peptides into amyloid plaques. The structural changes ...associated with the conversion of monomeric Aβ peptide building blocks into multimeric fibrillar β-strand aggregates remain unknown. Recently, we established that oxidation of the methionine-35 side chain to the sulfoxide (Met35red → Met35ox) significantly impedes the rate of aggregation and fibrillation of the Aβ peptide. To explore this effect at greater resolution, we carefully compared the 1H, 15N, and 13C NMR chemical shifts of four Aβ peptides that had the Met35 reduced or oxidized (Aβ(1−40)Met35red, Aβ(1−40)Met35ox, Aβ(1−42)Met35red, and Aβ(1−42)Met35ox). With the use of a special disaggregation protocol, the highly aggregation prone Aβ peptides could be studied at higher, millimolar concentrations (as required by NMR) in aqueous solution at neutral pH, remaining largely monomeric at 5 °C as determined by sedimentation equilibrium studies. The NOE, amide-NH temperature coefficients, and chemical shift indices of the 1Hα, 13Cα, and 13Cβ established that the four peptides are largely random, extended chain structures, with the Met35ox reducing the propensity for β-strand structure at two hydrophobic regions (Leu17−Ala21 and Ile31−Val36), and turn- or bendlike structures at Asp7−Glu11 and Phe20−Ser26. Additional NMR studies monitoring changes that occur during aging at 37 °C established that, along with a gradual loss of signal/noise, the Met35ox significantly hindered upfield chemical shift movements of the 2H NMR signals for the His6, His13, and His14 side chains. Taken together, the present NMR studies demonstrate that the Met35red → Met35ox conversion prevents aggregation by reducing both hydrophobic and electrostatic association and that the Aβ(1−40)Met35red, Aβ(1−40)Met35ox, Aβ(1−42)Met35red, and Aβ(1−42)Met35ox peptides may associate differently, through specific, sharp changes in structure during the initial stages of aggregation.
Abstract It has been proposed that deregulation of neuronal glycogen synthase kinase 3 (GSK3) activity may be a key feature in Alzheimer disease pathogenesis. We have previously generated transgenic ...mice that overexpress GSK3β in forebrain regions including dentate gyrus (DG), a region involved in learning and memory acquisition. We have found that GSK3 overexpression results in DG degeneration. To test whether tau protein modified by GSK3 plays a role in that neurodegeneration, we have brought GSK3 overexpressing mice to a tau knockout background. Our results indicate that the toxic effect of GSK3 overexpression is milder and slower in the absence of tau. Thus, we suggest that the hyperphosphorylated tau mediates, at least in part, the pathology observed in the brain of GSK3 overexpressing mice.
Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET ...is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway. OP449, a SET inhibitor, decreases AKT/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (P < 0.05), and IR phosphorylation was 4.5-fold higher in these mice (P < 0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (P < 0.05, for both, respectively). AKT and S6RP phosphorylation were 82% and 34% lower in OP449-treated tumors compared with controls (P < 0.05, P = 0.06, respectively). AKT and S6RP phosphorylation in response to insulin was 30% and 12% lower in cells, pre-treated with OP449, compared with control cells (P < 0.01, P < 0.05, respectively). However, even with decreased AKT/mTOR activation, body weights and composition, blood glucose and plasma insulin, glucose tolerance, serum triglyceride and cholesterol levels were similar between OP449-treated mice and controls. Xenografts and liver tissue from OP449-treated mice showed a 64% and 70% reduction in STAT5 activation, compared with controls (P < 0.01 and P = 0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells in vitro and in xenografts in the setting of hyperinsulinemia. OP449 led to the inhibition of AKT/mTOR signaling, albeit, not leading to metabolic derangements.
Function of tau protein in adult newborn neurons Fuster-Matanzo, Almudena; de Barreda, Elena Gómez; Dawson, Hana N. ...
FEBS letters,
September 17, 2009, Letnik:
583, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Levels of tau phosphorylation are high during the developmental period of intense neurite outgrowth, but decrease later. We here investigated whether tau protein plays a role in adult neurogenesis. ...First we demonstrate that new neurons generated in the subgranular zone express tau in a hyperphosphorylated form. Phospho-tau expression colocalized with doublecortin but not with glial fibrillary acidic protein, Ki67 or calbindin. The same was observed in the subventricular zone.
Tau knockout mice did not show a significant decrease in the number of doublecortin-positive cells, although a deficit in migration was observed. These findings suggest that basal tau phosphorylation present in adult animals is in part due to neurogenesis, and from
Tau knockout mice it seems that tau is involved in normal migration of new neurons.
Lymphoma is one of the most common malignant tumors in canine. Chemotherapy results in a high rate of remission; however, relapse and clinical drug resistance are usually seen within a year. Protein ...phosphatase 2A (PP2A) acts as a tumor suppressor and plays a critical role in mammalian cell transformation. Increased protein levels of SET, endogenous PP2A inhibitor, have been reported to correlate with poor prognosis in human leukemia. Here, we test the potential therapeutic role for a SET antagonist in canine lymphoma. We observed SET protein levels increased in multiple canine lymphoma cell lines compared with primary peripheral blood cells. A novel SET antagonist OP449 increased PP2A activity and effectively killed SET high-expressing canine lymphoma cells, but not SET low-expressing cells. Caspase-3 activation and enhanced Annexin V positive staining were observed after OP449 treatment, suggesting apoptotic cell death by OP449. Consistent with this, pan-caspase inhibitor Z-VAD-FMK blocked OP449 induced cell death. These data demonstrated the potential therapeutic application of SET antagonists for canine lymphoma.
Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to ...microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule-binding repeat encoded by exon 10 of the TAU gene. TAU gene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing. The mice recapitulate many of the disease hallmarks that are seen in patients with this mutation, including increased tau exon 10 inclusion in both mRNA and protein, motor and behavioral deficits, and tau protein accumulation in neurons and tufted astrocytes. Furthermore, these mice present with degeneration of the nigrostriatal dopaminergic pathway, suggesting a possible mechanism for parkinsonism in FTDP-17. Additionally, activated caspase-3 immunoreactivity in both neurons and astrocytes implicates the involvement of the apoptotic pathway in the pathology of these mice.
Apolipoprotein E (apoE) mimetic peptides are engineered fragments of the native apoE protein's LDL-receptor binding site that improve the outcomes following a brain injury and intestinal inflammation ...in a variety of models. The vicious cycle of enteric infections and malnutrition is closely related to environmental-driven enteric dysfunction early in life, and such chronic inflammatory conditions may blunt the developmental trajectories of children with worrisome and often irreversible physical and cognitive faltering. This window of time for microbiota maturation and brain plasticity is key to protecting cognitive domains, brain health, and achieving optimal/full developmental potential. This review summarizes the potential role of promising apoE mimetic peptides to improve the function of the gut-brain axis, including targeting the blood-brain barrier in children afflicted with malnutrition and enteric infections.
A growing body of evidence supports an important role for oxidative stress in the pathogenesis of Alzheimer's disease. Recently, a number of papers have shown a synergistic neurotoxicity of amyloid β ...peptide and cupric ions. We hypothesized that complexes of cupric ions with neurotoxic amyloid β peptides (Aβ) can stimulate copper-mediated free radical formation. We found that neurotoxic Aβ (1-42), Aβ (1-40), and Aβ (25-35) stimulated copper-mediated oxidation of ascorbate, whereas nontoxic Aβ (40-1) did not. Formation of ascorbate free radical was significantly increased by Aβ (1-42) in the presence of ceruloplasmin. Once cupric ion is reduced to cuprous ion, it can be oxidized by oxygen to generate superoxide radical or it can react with hydrogen peroxide to form hydroxyl radical. Hydrogen peroxide greatly increased the oxidation of cyclic hydroxylamines and ascorbate by cupric–amyloid β peptide complexes, implying redox cycling of copper ions. Using the spin-trapping technique, we have shown that toxic amyloid β peptides led to a 4-fold increase in copper-mediated hydroxyl radical formation. We conclude that toxic Aβ peptides do indeed stimulate copper-mediated oxidation of ascorbate and generation of hydroxyl radicals. Therefore, cupric–amyloid β peptide-stimulated free radical generation may be involved in the pathogenesis of Alzheimer's disease.
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