Dataset Information

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE.

ABSTRACT: Vitamin B12 (cobalamin, Cbl) is indispensable for proper brain development and functioning, suggesting that it has neurotrophic effects beside its well-known importance in metabolism. The molecular basis of these effects remains hypothetical, one of the reasons being that no efficient cell model has been made available for investigating the consequences of B12 cellular deficiency in neuronal cells. Here, we designed an approach by stable transfection of NIE115 neuroblastoma cells to impose the anchorage of a chimeric B12-binding protein, transcobalamin-oleosin (TO) to the intracellular membrane. This model produced an intracellular sequestration of B12 evidenced by decreased methyl-Cbl and S-adenosylmethionine and increased homocysteine and methylmalonic acid concentrations. B12 deficiency affected the proliferation of NIE115 cells through an overall increase in catalytic protein phosphatase 2A (PP2A), despite its demethylation. It promoted cellular differentiation by improving initial outgrowth of neurites and, at the molecular level, by augmenting the levels of proNGF and p75(NTR). The up-regulation of PP2A and pro-nerve growth factor (NGF) triggered changes in ERK1/2 and Akt, two signaling pathways that influence the balance between proliferation and neurite outgrowth. Compared with control cells, a 2-fold increase of p75(NTR)-regulated intramembraneous proteolysis (RIP) was observed in proliferating TO cells (P < 0.0001) that was associated with an increased expression of two tumor necrosis factor (TNF)-alpha converting enzyme (TACE) secretase enzymes, Adam 10 and Adam 17. In conclusion, our data show that B12 cellular deficiency produces a slower proliferation and a speedier differentiation of neuroblastoma cells through interacting signaling pathways that are related with increased expression of PP2A, proNGF, and TACE.

SUBMITTER: Battaglia-Hsu SF

PROVIDER: S-EPMC2788478 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundVitamin B12 deficiency during pregnancy has been associated with adverse maternal and infant health outcomes. Few prospective studies have investigated vitamin B12 status early in pregnancy, and its links to infant vitamin B12 status, particularly in India where the burden of vitamin B12 deficiency is estimated to be the highest globally. The objective of this study was to examine the associations of maternal vitamin B12 biomarkers with neonatal vitamin B12 status.MethodsPregnant women (~12 weeks' gestation) were enrolled in a perinatal cohort study in Bangalore, India. Total vitamin B12, methylmalonic acid (MMA), and homocysteine concentrations were evaluated in maternal samples at enrollment and in neonates at birth using cord blood. Linear and binomial regression models were used to evaluate the associations of maternal vitamin B12 biomarkers with neonatal vitamin B12 status and perinatal outcomes.ResultsA total of 63.2% of women had vitamin B12 deficiency (<148 pmol/L), 87.2% had vitamin B12 insufficiency (<221 pmol/L), and 47.3% had impaired vitamin B12 status (vitamin B12<148 pmol/L and MMA>0.26μmol/L) at enrollment; 40.8% of neonates had vitamin B12 deficiency, 65.6% were insufficiency, and 38.1% had impaired vitamin B12 status at birth. Higher maternal vitamin B12 concentrations at enrollment were associated with increased neonatal vitamin B12 concentrations (β(SE): 0.40 (0.05); p<0.0001) and lower risk of neonatal vitamin B12 deficiency (Risk Ratio [RR]: 0.53; 95% CI: [0.43, 0.65]; p<0.0001). Maternal vitamin B12 deficiency (RR: 1.97 [1.43, 2.71]; p<0.001), insufficiency (RR: 2.18 [1.23, 3.85]; p = 0.007), and impaired vitamin B12 status (RR: 1.49 [1.13, 1.97]; p = 0.005) predicted a two-fold increase in the risk of neonatal vitamin B12 deficiency at birth.ConclusionsThe prevalence of vitamin B12 deficiency was high early in pregnancy and predicted neonatal vitamin B12 status. Future research is needed to determine the role of vitamin B12 in the development of pregnancy and infant outcomes, and to inform screening and interventions to improve maternal and child health.

Project description:BackgroundPhysical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age-related chronic diseases, including in the musculo-skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models.MethodsWe analysed a subset of the Singapore Longitudinal Aging Study and stratified 238 participants based on age and Fried frailty criteria. Levels of methyl-malonic acid (MMA), a marker for vitamin B12 deficiency, and amnionless, the vitamin B12 co-receptor that anchors the vitamin B12 transport complex to the membrane of epithelial cells, were measured in plasma. In addition, vitamin B12 levels and the molecular mechanisms of vitamin B12 uptake and excretion were analysed in ileum, kidney, liver, and blood using a rat model of natural aging where nutritional intake is fully controlled.ResultsWe demonstrate that aging and frailty are associated with a higher prevalence of functional vitamin B12 deficiency that can be detected by increased levels of MMA in blood (ρ = 0.25; P = 0.00013). The decline in circulating vitamin B12 levels is recapitulated in a rat model of natural aging where food composition and intake are stable. At the molecular level, these perturbations involve altered expression of amnionless in the ileum and kidney. Interestingly, we demonstrate that amnionless can be detected in serum where its levels increase during aging in both rodents and human (P = 3.3e-07 and 9.2e-07, respectively). Blood amnionless levels negatively correlate with vitamin B12 in rats (r2 = 0.305; P = 0.0042) and positively correlate with the vitamin B12 deficiency marker MMA in humans (ρ = 0.22; P = 0.00068).ConclusionsOur results demonstrate that aging and frailty cause intrinsic vitamin B12 deficiencies, which can occur independently of nutritional intake. Mechanistically, vitamin B12 deficiency involves the physio-pathological decline of both the intestinal uptake and the renal reabsorption system for vitamin B12. Finally, amnionless is a novel biomarker which can detect perturbed vitamin B12 bioavailability during aging and physical frailty.

Dataset Information

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets