WRAP53 Unwrapped; Roles in Nuclear Architecture and Cancer

WRAP53 is a gene of multiple functions; it encodes for a natural antisense transcript that regulates the actions of the tumour suppressor p53, and it gives rise to a protein with oncogenic properties that is important for Cajal body formation and maintenance. Natural antisense transcripts are a group of regulatory RNAs implicated in many aspects of eukaryotic gene expression including transcription, RNA localization, translation and RNA stability. Even though up to 70% of all human genes may overlap in an antisense fashion, little is known about their biological significance. In this work, we have identified a natural antisense transcript of p53 that regulates the steady-state levels of endogenous p53 mRNA and the induction of p53 in response to DNA damage. p53 is a transcription factor that upon DNA damage and other types of cellular stress induces either growth arrest or apoptosis. The significance of p53 in cancer is clearly demonstrated by the fact that approximately 50% of human cancers carry alterations within the p53 gene and that the remaining tumours frequently show other defects within the p53 pathway. Our discovery that WRAP53 stabilizes the p53 mRNA by targeting its 5'untranslated region, reveals a novel pathway for p53 regulation and also suggests a novel therapeutic strategy for cancer treatment. The WRAP53 gene also codes for a protein that has a major role in Cajal body integrity and function. Cajal bodies are nuclear structures implicated in diverse functions such as maturation of the splicing machinery and telomere biogenesis. The WRAP53 protein has been shown to direct small Cajal body-specific RNAs, including the TERT, the RNA part of the telomerase complex, to these nuclear structures. We reveal that WRAP53 in addition directs the survival of motor neuron (SMN) complex to Cajal bodies and that WRAP53 is essential for Cajal body integrity. Our findings further highlight the role of WRAP53 as a Cajal body recruitment factor and contribute to our understanding of the molecular mechanisms behind Cajal body formation. Interestingly, we also find that WRAP53 has oncogenic properties and is overexpressed in human cancers in comparison to primary cells. Moreover, knockdown of WRAP53 leads to massive apoptosis through the intrinsic mitochondrial pathway. Human cancer cells are more sensitive to WRAP53 depletion as compared to normal human fibroblasts, identifying WRAP53 as a novel therapeutic target in cancer. Altogether, our findings suggest an important role of the WRAP53 RNA and protein in tumourigenesis with great implications in cancer therapy

Cross-Platform Comparison of Untargeted and Targeted Lipidomics Approaches on Aging Mouse Plasma.

Lipidomics - the global assessment of lipids - can be performed using a variety of mass spectrometry (MS)-based approaches. However, choosing the optimal approach in terms of lipid coverage, robustness and throughput can be a challenging task. Here, we compare a novel targeted quantitative lipidomics platform known as the Lipidyzer to a conventional untargeted liquid chromatography (LC)-MS approach. We find that both platforms are efficient in profiling more than 300 lipids across 11 lipid classes in mouse plasma with precision and accuracy below 20% for most lipids. While the untargeted and targeted platforms detect similar numbers of lipids, the former identifies a broader range of lipid classes and can unambiguously identify all three fatty acids in triacylglycerols (TAG). Quantitative measurements from both approaches exhibit a median correlation coefficient (r) of 0.99 using a dilution series of deuterated internal standards and 0.71 using endogenous plasma lipids in the context of aging. Application of both platforms to plasma from aging mouse reveals similar changes in total lipid levels across all major lipid classes and in specific lipid species. Interestingly, TAG is the lipid class that exhibits the most changes with age, suggesting that TAG metabolism is particularly sensitive to the aging process in mice. Collectively, our data show that the Lipidyzer platform provides comprehensive profiling of the most prevalent lipids in plasma in a simple and automated manner

Impact of Zinc Excess on Germination, Growth Parameters and Oxidative Stress of Sweet Basil (Ocimum basilicum L.)

In the present study, the effects of elevated zinc concentrations on germination, physiological and biochemical parameters were investigated in basil (Ocimum basilicum L.). Results indicate that zinc excess (1–5 mM ZnSO4) did not affect germination process, but it drastically reduced vigor index and radicle elongation, and induced oxidative stress. Exposure of basil plants to 400 and 800 µM Zn decreased aerial parts and roots dry biomass, root length and leaf number. Under these conditions, the reduction of plant growth was associated with the formation of branched and abnormally shaped brown roots. Translocation factor \u3c 1 and bioconcentration factor \u3e 1 was observed for 100 µM Zn suggested the possible use of basil as a phytostabiliser. Excess of Zn supply (\u3e 100 µM) decreased chlorophyll content, total phenol and total flavonoid contents. Additionally, an increased TBARS levels reflecting an oxidative burst was observed in Zn-treated plants. These findings suggest that excess Zn adversely affects plant growth, photosynthetic pigments, phenolic and flavonoid contents, and enhances oxidative stress in basil plants

Enhanced accumulation of root hydrogen peroxide is associated with reduced antioxidant enzymes under isoosmotic NaCl and Na2SO4 salinities

The inhibitory effect of salt stress on lettuce is one of the main reasons for the reduction of plant growth and crop productivity. In the present study, the response of two lettuce varieties Verte and Romaine to isoosmotic NaCl and Na2SO4 treatments were examined. Both varieties were grown in pots containing nutrient Hoagland solution with or without 100 mM NaCl or 77 mM Na2SO4. Relative growth rate (RGR), hydraulic parameters, root ion content, proline and several antioxidant activities in roots were measured after 12 days of treatment. After prolonged exposure to salt stress, relative growth rate and water content of lettuce significantly decreased. Roots accumulated high level of Na+ under both salts, whereas the accumulation of K+ and Ca2+ decreased. High level of Na+ inside the cells inhibited the K+ uptake and resulted in increased K+/Na+ ratio. In addition, salt stress also caused an increase in the accumulation of proline. This result suggests that proline may play a crucial role in protecting lettuce under salt stress especially in response to Na2SO4 treatment. Membrane damage estimated by electrolyte leakage (EL) increased especially in response to Na2SO4 treatment in both varieties, but Verte had significantly lower EL relative to Romaine under 100 mM NaCl. A reduction in the activities of CAT in both varieties under 100 mM, and GPX activity in Verte under Na2SO4 treatment coincided with an increase in H2O2 level, indicative of cellular damage and a general depression of the antioxidant enzymatic system in lettuce roots.Keywords: Lettuce, NaCl, Na2SO4, RGR, mineral nutrition, antioxidant activities, prolin

Optimal setting of time-and-level-of-use prices for an electricity supplier

International audienceThis paper presents a novel price setting optimization problem for an electricity supplier in the smart grid. In this framework the supplier provides electricity to a residential load aggregator using Time-and Level-of-Use prices (TLOU). TLOU is an energy pricing structure recently introduced in the literature, where the prices vary depending on the time and the level of consumption. This problem is formulated as a bilevel optimization problem, in which the supplier sets the prices that maximize the profit in a demand response context, anticipating the reaction of a residential load aggregator that minimizes total cost. These decisions are made in a competitive environment, while explicitly considering the aggregator's load shifting preferences and the level of consumption, and ensuring a user-friendly price structure. The optimization problem is reformulated as a single-level problem to be solved using off-the shelf solvers. We present computational experiments to validate the performance of TLOU, and provide insights on the relationship between the user's demand flexibility, the capacity profile and the resulting structure of prices. We show that the supplier's economical benefit is increased up to 10% through the implementation of this type of demand response program, while providing savings of up to 6% for the consumers

CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer

SCF (Skp1/Cul1/F‐box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F‐box protein, FBXO28 that controls MYC‐dependent transcription by non‐proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2‐mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F‐box mutant unable to support MYC ubiquitylation results in an impairment of MYC‐driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK‐FBXO28‐MYC axis as a potential molecular drug target in MYC‐driven cancers, including breast cancer

WRAP53 Is Essential for Cajal Body Formation and for Targeting the Survival of Motor Neuron Complex to Cajal Bodies

The WRAP53 protein regulates the formation and maintenance of Cajal bodies (nuclear sub-organelles), as well as directs the recruitment of nuclear factors to Cajal bodies